Intro
Dame Louise Napier Johnson was the infamous mistress of Dr. Abdus Salam. They met in 1962, at some antinuclear proliferation meeting in London, Louise was only 20 years old, and Salam was 36, and an accomplished Physics professors at Imperial College London, Louise Johnson, then a physics undergraduate at University College London (UCL), who was helping with the meeting’s administration.

After her PhD, she moved to the laboratory of Frederic M. Richards at Yale University for postdoctoral research in 1966. At Yale she worked as part of a team with Frederic M. Richards and Hal Wyckoff on the crystal structure of another enzyme, ribonuclease, which was solved shortly after she left: the fourth protein structure solved. After her post-doctoral year at Yale, she returned to the UK in 1967 and took up the post of Departmental Demonstrator in the Department of Zoology, University of Oxford.

By 1968, this love affair was in full swing, and secretly. However, Dr. Abdus Salam was still married to Amtul Hafeez (she died in 2007, his first-cousin), she was the sister of Col. G.M. Iqbal. Allegedly, Salam and Louise Johnson were married in a Qadiani wedding in London in 1968. An unlikely witness was Paul Mathews, Salam’s long-time research partner and professor at Imperial (See Fraser, “Cosmic Anger”, page 230-231).

Her son was born in 1974 (Umar) and a daughter was born in 1982 (Saeeda). Both of these children are shunned by the Ahmadiyya Movement. In 1973 she was appointed University Lecturer, a post which was associated with Somerville College, Oxford. She became an Additional Fellow of the college and the Janet Vaughan Lecturer. She was now able to expand her team of graduate students and post-doctoral researchers. The phosphorylase work developed and by 1978 the team had discovered its structure and were able to work on its biological control properties.

She was David Phillips Professor of Molecular Biophysics at the University of Oxford from 1990 to 2007, and later an emeritus professor.

She died in 2012.

 

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Her son
Who is Umar Salam? son of Dr. Abdus Salam? – ahmadiyyafactcheckblog

Umar Salam is the son of Dr. Abdus Salam and his mistress, Dr. Dame Louise Napier Johnson. He was born in 1974 in what seems to be London.
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Her daughter
https://www.theguardian.com/science/2012/oct/10/louise-johnson

A daughter was born in 1982 (Saeeda).
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1940
https://en.wikipedia.org/wiki/Louise_Johnson
Dame Louise Napier Johnson. 26 September 1940—25 September 2012 | Biographical Memoirs of Fellows of the Royal Society (royalsocietypublishing.org)

Louise Johnson was born on 26 September 1940 in Worcester, the second of the three daughters of George Edmund Johnson (1904–1992), a former wool broker then serving in the RAF (in which he reached the rank of Wing Commander), and his wife Elizabeth Minna, née King (1914–1992). The family moved around the country following George Johnson’s RAF postings, from Exton to Market Harborough, and then to London in 1946. Louise attended Putney High School and then a school in Aberdeen, where the family lived for three years in the early 1950s, before moving to Wimbledon High School for Girls on their return to London. There she excelled, eventually becoming head girl. Her headmistress was an important inspiration to her. Both her school and family put a great value on girls’ education. Her mother had obtained a degree from University College London (UCL), and it was at the same institution that Louise studied for a BSc degree in physics, graduating in 1962.
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1952-1959
https://en.wikipedia.org/wiki/Louise_Johnson

Johnson attended Wimbledon High School for Girls from 1952 to 1959, where girls were encouraged to study science and to pursue useful careers.
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1959
https://en.wikipedia.org/wiki/Louise_Johnson

 

Her mother had read biochemistry and physiology at University College London in the 1930s and was supportive of Johnson’s decision to pursue a scientific career. She went to University College London in 1959 to read Physics and coming from an all-girls school, she was surprised to find herself one of only four girls in a class of 40.

She took theoretical physics as her third-year option and graduated with a 2.1 degree. Whilst working at the Atomic Energy AuthorityHarwell, on neutron diffraction, during one of her vacations, she met Uli Arndt, an instrument scientist, who worked at the Royal Institution, London. She was impressed by the work taking place there and in 1962 she moved to the Royal Institution to do a PhD in biophysics.[citation needed] Her graduate supervisor was David Chilton Phillips, whose team was working on the crystal structure of lysozyme.[citation needed] Her first task was to determine the structure of a sugar molecule, N-Acetylglucosamine, using x-ray diffraction, which she solved within a year.
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1962
https://en.wikipedia.org/wiki/Louise_Johnson

in 1962 she moved to the Royal Institution to do a PhD in biophysics.[citation needed] Her graduate supervisor was David Chilton Phillips, whose team was working on the crystal structure of lysozyme.[citation needed] Her first task was to determine the structure of a sugar molecule, N-Acetylglucosamine, using x-ray diffraction, which she solved within a year. She then moved onto the study of the substrate binding to the protein lysozyme and was part of the team, that discovered the structure of the enzyme lysozyme; this was the third protein structure ever solved by x-ray crystallography, and the first enzyme. She was awarded her PhD in 1965.[1]

She also met Dr. Abdus Salam in 1962 at a antinuclear proliferation meeting in London in 1962, Salam had met Louise Johnson, then a physics undergraduate at University College London (UCL), who was helping with the meeting’s administration. It was what the French call un coup de foudre, an emotional lightning strike, such as Salam had not experienced since seeing the inaccessible Urmilla at Government College, Lahore, some twenty years before. Louise was only 20 years old, and Salam was 36. It should be noted that Ahmadiyya literature never mentions his second wife (girlfriend) and those circumstances (see the Al-Nahl of 1997, which has 200+ pages of data on Dr. Salam, however, they barely mention his second wife and those 2 amazing kids, see page 200, it is nevertheless from a Pakistani newspaper). Dr. Dame Louise Napier Johnson was never his wife, instead a life-long girlfriend.
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1966
https://en.wikipedia.org/wiki/Louise_Johnson

She completed her PhD in 1966, after her PhD, she moved to the laboratory of Frederic M. Richards at Yale University for postdoctoral research in 1966. At Yale she worked as part of a team with Frederic M. Richards and Hal Wyckoff on the crystal structure of another enzyme, ribonuclease, which was solved shortly after she left: the fourth protein structure solved.[7]

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1967
https://en.wikipedia.org/wiki/Louise_Johnson

After her post-doctoral year at Yale, she returned to the UK in 1967 and took up the post of Departmental Demonstrator in the Department of Zoology, University of Oxford. The Professor of Zoology, J.W.R. Pringle, saw zoology as extending from animal studies to molecular studies, and had been partly responsible for bringing David Phillips to Oxford as Professor of Molecular Biophysics. Johnson was able to combine teaching with independent research and continued her work on lysozyme and new crystal studies on other enzymes.


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1968

By 1968, this love affair was in full swing, and secretly. However, Dr. Abdus Salam was still married to Amtul Hafeez (she died in 2007, his first-cousin), she was the sister of Col. G.M. Iqbal. Allegedly, Salam and Louise Johnson were married in a Qadiani wedding in London in 1968. An unlikely witness was Paul Mathews, Salam’s long-time research partner and professor at Imperial (See Fraser, “Cosmic Anger”, page 230-231). 
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1973
https://en.wikipedia.org/wiki/Louise_Johnson

In 1973 she was appointed University Lecturer, a post which was associated with Somerville College, Oxford. She became an Additional Fellow of the college and the Janet Vaughan Lecturer. She was now able to expand her team of graduate students and post-doctoral researchers.
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1974
https://www.theguardian.com/science/2012/oct/10/louise-johnson

His son was born in 1974 (Umar) and a daughter was born in 1982 (Saeeda). Both of these children are shunned by the Ahmadiyya Movement.
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1976
Dame Louise Napier Johnson. 26 September 1940—25 September 2012 | Biographical Memoirs of Fellows of the Royal Society (royalsocietypublishing.org)

Figure 3.

Figure 3. Zoology department, University of Oxford, 1976. Front row: Louise Johnson (third from left), D. C. Phillips (centre), John Pringle (left of D. C. Phillips). Second row: K. Wilson (seventh from left), Irene Weber (sixth from right).
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1978

The phosphorylase work developed and by 1978 the team had discovered its structure and were able to work on its biological control properties. Glycogen phosphorylase is found in muscle and is responsible for mobilising the energy store of glycogen to provide fuel to sustain muscle contraction. In resting muscle the enzyme is switched off to prevent wasteful degradation of the fuel but in response to nervous or hormonal signals the enzyme is switched on almost simultaneously to generate the energy supply. Her research was directed towards understanding the molecular basis of the biological properties of control and catalytic mechanism. Her team used the bright x-ray source generated at the Synchrotron Radiation Source at Daresbury, which provided data that could not be obtained with the home source.
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1982
https://en.wikipedia.org/wiki/Louise_Johnson
https://www.theguardian.com/science/2012/oct/10/louise-johnson

Her daughter was born in 1982 (Saeeda).
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1990-2007

She was David Phillips Professor of Molecular Biophysics at the University of Oxford from 1990 to 2007, and later an emeritus professor.[6]

Figure 6.

Figure 6. David Phillips and Louise Johnson at the Ciba Foundation in 1991 (with Ben Bax in the background.) (Photograph copyright unknown.)

Figure 7.

Figure 7. Chatting with Dorothy Hodgkin shortly after Louise’s election as a Fellow of the Royal Society and to the David Phillips professorship of molecular biophysics, 1990. (Photograph copyright Norman McBeath.)

Figure 8.

Figure 8. Louise with Eddy Fischer (left) and Ernst Helmreich (right) on the occasion of a symposium marking her retirement from the David Phillips professorship, September 2007. (Photograph courtesy of Janos Hajdu.) (Online version in colour.)
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2012
https://en.wikipedia.org/wiki/Louise_Johnson

She died on 25 September 2012 in Cambridge, England, aged 71.[18][5][19]

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https://en.wikipedia.org/wiki/Louise_Johnson

Dame Louise Napier JohnsonDBE FRS (26 September 1940 – 25 September 2012[5]), was a British biochemist and protein crystallographer. She was David Phillips Professor of Molecular Biophysics at the University of Oxford from 1990 to 2007, and later an emeritus professor.[6] She was married to Pakistani nuclear physicist and a Nobel Prize-laureate Abdus Salam.

Education

[edit]

Johnson attended Wimbledon High School for Girls from 1952 to 1959, where girls were encouraged to study science and to pursue useful careers. Her mother had read biochemistry and physiology at University College London in the 1930s and was supportive of Johnson’s decision to pursue a scientific career. She went to University College London in 1959 to read Physics and coming from an all-girls school, she was surprised to find herself one of only four girls in a class of 40.

She took theoretical physics as her third-year option and graduated with a 2.1 degree. Whilst working at the Atomic Energy AuthorityHarwell, on neutron diffraction, during one of her vacations, she met Uli Arndt, an instrument scientist, who worked at the Royal Institution, London. She was impressed by the work taking place there and in 1962 she moved to the Royal Institution to do a PhD in biophysics.[citation needed] Her graduate supervisor was David Chilton Phillips, whose team was working on the crystal structure of lysozyme.[citation needed] Her first task was to determine the structure of a sugar molecule, N-Acetylglucosamine, using x-ray diffraction, which she solved within a year. She then moved onto the study of the substrate binding to the protein lysozyme and was part of the team, that discovered the structure of the enzyme lysozyme; this was the third protein structure ever solved by x-ray crystallography, and the first enzyme. She was awarded her PhD in 1965.[1]

Career

[edit]

After her PhD, she moved to the laboratory of Frederic M. Richards at Yale University for postdoctoral research in 1966. At Yale she worked as part of a team with Frederic M. Richards and Hal Wyckoff on the crystal structure of another enzyme, ribonuclease, which was solved shortly after she left: the fourth protein structure solved.[7]

After her post-doctoral year at Yale, she returned to the UK in 1967 and took up the post of Departmental Demonstrator in the Department of Zoology, University of Oxford. The Professor of Zoology, J.W.R. Pringle, saw zoology as extending from animal studies to molecular studies, and had been partly responsible for bringing David Phillips to Oxford as Professor of Molecular Biophysics. Johnson was able to combine teaching with independent research and continued her work on lysozyme and new crystal studies on other enzymes. In 1972 she received some crystals of glycogen phosphorylase and this was the beginning of a major chapter in her research career. She began a detailed x-ray crystallographic analysis of the protein, which was eight times larger than lysozyme and much larger than any of the other proteins whose structures had been solved at that time.

In 1973 she was appointed University Lecturer, a post which was associated with Somerville College, Oxford. She became an Additional Fellow of the college and the Janet Vaughan Lecturer. She was now able to expand her team of graduate students and post-doctoral researchers. The phosphorylase work developed and by 1978 the team had discovered its structure and were able to work on its biological control properties. Glycogen phosphorylase is found in muscle and is responsible for mobilising the energy store of glycogen to provide fuel to sustain muscle contraction. In resting muscle the enzyme is switched off to prevent wasteful degradation of the fuel but in response to nervous or hormonal signals the enzyme is switched on almost simultaneously to generate the energy supply. Her research was directed towards understanding the molecular basis of the biological properties of control and catalytic mechanism. Her team used the bright x-ray source generated at the Synchrotron Radiation Source at Daresbury, which provided data that could not be obtained with the home source.[7] She was David Phillips Professor in Molecular Biophysics, University of Oxford, in 1990–2007.

Johnson’s lab at Oxford solved and studied many other protein structures, and she is a depositor on 100 PDB entries including many forms of glycogen phosphorylase[8] and of cell cycle CDK/cyclin complexes[9] As well as carrying out cutting-edge research, she nurtured numerous careers, training a generation of crystallographers in Oxford who themselves now train future leaders across the world.[10] Together with Tom Blundell, she wrote an influential textbook on protein crystallography.[11] She was Director of Life Sciences at Diamond Light Source, 2003–2008, and was a Fellow of Diamond Light Source, 2008–2012. Diamond Light Source is the UK’s national synchrotron facility at Harwell, Oxfordshire.[12]

Honours

[edit]

She was appointed Dame Commander of the Order of the British Empire (DBE) in 2003.[citation needed] She was a Fellow of Corpus Christi College, Oxford and an Honorary Fellow of Somerville College, Oxford.[13] She received a number of honorary degrees, including: Hon DSc University of St Andrews, 1992; Hon DSc University of Bath, 2004; Hon DSc Imperial College London, 2009; Hon DSc University of Cambridge, 2010. She was elected a Fellow of the Royal Society[14] (FRS) in 1990; an Associate Fellow of the Third World Academy of Science, 2000; a Foreign Associate of the US National Academy of Sciences, 2011.[15][16]

Personal life

[edit]

Louise Napier Johnson was born on 26 September 1940 at South Bank Nursing Home, Worcester, as the second of three daughters of George Edmund Johnson (1904–1992), a wool broker then serving in the Royal Air Force, and his wife, Elizabeth Minna, née King (1914–1992). The family was living at White Cottage, Rushwick, near Worcester, at the time.[17]

Johnson married the Pakistani theoretical physicist Abdus Salam in 1968.[5] He later shared the Nobel Prize for Physics in 1979 for his work on electroweak unification. They had two children: a son born in 1974 and a daughter born in 1982. Johnson’s husband died in 1996. She died on 25 September 2012 in Cambridge, England, aged 71.[18][5][19]

References

[edit]

  1. Jump up to:a b Johnson, Louise Napier (1965). An X-ray crystallographic study of N-acetylglucosamine and its relation to lysozymelondon.ac.uk (PhD thesis). University of LondonOCLC 1006071943.
  2. ^ “Fred Richards on Academic Tree”.
  3. ^ Owen, David Jonathan (1994). Molecular studies on phosphorylase kinasesolo.bodleian.ox.ac.uk (DPhil thesis). University of Oxford. OCLC 55697925EThOS uk.bl.ethos.240633.
  4. ^ Johnson, L. N.Phillips, D. C. (1964). “Crystal Structure of N-Acetylglucosamine”Nature202 (4932): 588. Bibcode:1964Natur.202..588Jdoi:10.1038/202588a0PMID 14195059S2CID 4277260.
  5. Jump up to:a b c “ICTP – In Memoriam”. Ictp.it. 26 September 1940. Archived from the original on 16 November 2012. Retrieved 6 October 2012.
  6. ^ Sansom, M. (2012). “Louise Johnson (1940–2012)”Nature490 (7421): 488. Bibcode:2012Natur.490..488Sdoi:10.1038/490488aPMID 23099399.
  7. Jump up to:a b Louise N. Johnson, “Clever Women”, unpublished autobiographical notes, deposited with the papers of L.N. Johnson, at the Bodleian Library, University of Oxford.
  8. ^ Barford, D.; Johnson, L. N. (1989). “The allosteric transition of glycogen phosphorylase”. Nature340 (6235): 609–616. Bibcode:1989Natur.340..609Bdoi:10.1038/340609a0PMID 2770867S2CID 132865.
  9. ^ Honda, R.; Lowe, E. D.; Dubinina, E.; Skamnaki, V.; Cook, A.; Brown, N. R.; Johnson, L. N. (2005). “The structure of cyclin E1/CDK2: Implications for CDK2 activation and CDK2-independent roles”The EMBO Journal24 (3): 452–463. doi:10.1038/sj.emboj.7600554PMC 548659PMID 15660127.
  10. ^ “Louise Johnson Remembered”Department of Biochemistry, University of Oxford. Retrieved 20 April 2015.
  11. ^ Blundell, TL; Johnson, LN (1976), Protein Crystallography, Academic Press, ISBN 978-0121083502
  12. ^ Diamond Light Source.
  13. ^ University of Oxford (September 2009). “Professors Emeritus”. University of Oxford Calendar 2009–2010Oxford University Press. p. 203. ISBN 978-0-19-956692-1.
  14. ^ Barford, David; Blundell, Thomas L. (2022). “Dame Louise Napier Johnson. 26 September 1940—25 September 2012”Biographical Memoirs of Fellows of the Royal Society72: 221–250. doi:10.1098/rsbm.2021.0038S2CID 247191024.
  15. ^ Order of Service for Louise Johnson, 2012, deposited with the papers of L.N. Johnson at the Bodleian Library, University of Oxford
  16. ^ Staff (8 October 2012). “Obituaries: Professor Dame Louise Johnson”. London: The Telegraph. Retrieved 22 October 2012.
  17. ^ Elspeth F. Garman, “Johnson, Dame Louise Napier (1940–2012)”, Oxford Dictionary of National Biography (Oxford, UK: Oxford University Press, 2016) Retrieved 21 February 2016.
  18. ^ Lancet obituary Retrieved 16 January 2018.
  19. ^ Tom Blundell (10 October 2012). “Dame Louise Johnson obituary | guardian.co.uk”The Guardian. London. Retrieved 10 October 2012.

 

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Dame Louise Johnson obituary | Biochemistry and molecular biology | The Guardian

 

Dame Louise Johnson obituary

This article is more than 11 years old
Pioneering molecular biologist who shed light on how enzymes, nature’s catalysts, do their work

During a special meeting at the Royal Institution in London in 1965, the first structure of an enzyme, lysozyme, was unveiled by David Phillips. The fully extended polypeptide chain hung down from the high ceiling, coming close to Phillips. In front of him was a much more compact model, defined by X-ray crystallography, of the intricately folded chain. Both represented a protein that was in real life 100m times smaller. Phillips and his colleagues identified a well-defined groove in which evolution had suggestively placed amino acid sidechains.

The most memorable part of that day was the appearance of Louise Johnson, a young graduate student, who stunned us all by describing how the enzyme bound its substrates and selectively cleaved the polysaccharide components of bacterial cell walls, giving rise to its anti-microbial properties, first described by Alexander Fleming in the 1920s. This was the birth of structural enzymology, the beginnings of a continuing investigation of the detailed structures and mechanisms of nature’s catalysts.

Louise, who has died aged 71, continued to be in the vanguard of enzymology throughout her life. After completing her PhD, she moved to Yale in 1966 to work with the eminent biochemist and biophysicist Fred Richards. She returned to the UK in 1967 to rejoin Phillips, who had just been appointed to Oxford University as professor of molecular biophysics.

In Oxford she began to work on another extremely challenging project, the structure of the regulatory enzyme glycogen phosphorylase. After more than 20 years of work she was able to describe the structure of this magnificent enzyme and to explain its regulation.

Louise was born in Worcester. After attending Wimbledon high school for girls, she studied physics at University College London and then moved to the Royal Institution, where she completed her PhD in 1966. Her appointment at Oxford in 1967 was as a university demonstrator and lecturer in biophysics at Somerville College; she became a university lecturer and fellow of Somerville in 1973. On the retirement of Phillips in 1990, she was his obvious successor, becoming professor of molecular biophysics and professorial fellow at Corpus Christi College. In the same year her work was recognised by election to the Royal Society. She was made a dame in 2003.

In 1968, Louise married Abdus Salam, the brilliant Pakistani physicist and future Nobel laureate. They had two children, Umar in 1974 and Sayyeda in 1982.

I discovered Louise’s grasp of physics as well as biology when Phillips asked us to write a review of protein crystallography for Biennial Reviews of Science, Technology and Medicine in July 1971, a task he had failed to start and for which the manuscript was overdue. Louise and I both sacrificed our holidays and Louise completed her sections with brilliant insights into this complex, multidisciplinary research technique. The editor accepted only our concluding section as the review and suggested we write a textbook. This we did, after negotiating a large advance with which Louise bought a horse, as one of her passions was riding. She wrote sections of the book while she was pregnant with Umar, and it was eventually published in 1976. It was reissued in 2006.

Louise’s interest in physical techniques led her to accept the role of director for life sciences at the Diamond Light Source, the UK’s national synchrotron science facility, in 2003. She championed advances made possible by this powerful new source of X-rays, not only in structural biology at the molecular level, but also for X-ray imaging of whole cells.

But Louise never lost her interest in understanding cell regulation through phosphorylation, including the role of protein kinases in the cell cycle. The structures she defined have provided molecular and cell biologists not only with a general model as to how the protein kinases are regulated, but also the knowledge to guide the design of cancer drugs that are now in clinical trials.

Louise had a passionate interest in science in developing countries. She played a major role as an associate member of the Third World Academy of Sciences, particularly in influencing the development of science in Islamic countries, lecturing in Iran and Pakistan, and supporting the development of Sesame, the new synchrotron in Jordan. She was a generous person and a wonderful teacher, stimulating and inspiring a generation of structural biologists in the UK and elsewhere, who will continue her philosophy of advancing science in a multidisciplinary and international context.

Abdus died in 1996. Louise is survived by her children.

 Louise Napier Johnson, molecular biophysicist, born 26 September 1940; died 25 September 2012
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Dame Louise Napier Johnson. 26 September 1940—25 September 2012 | Biographical Memoirs of Fellows of the Royal Society (royalsocietypublishing.org)

Memoirs

Dame Louise Napier Johnson. 26 September 1940—25 September 2012

Abstract

Inline Graphic

Louise Johnson was a leading architect of protein crystallography and structural enzymology. She pioneered the application of the technique to understand how enzymes function at the molecular level. Much of our current knowledge of how enzymes catalyse chemical reactions with high specificity and how their activities are regulated, especially by cooperative allosteric transitions and reversible protein phosphorylation, has its origins in Louise’s research on lysozyme, glycogen phosphorylase and protein kinases. Louise helped pioneer Laue protein crystallography as a method to elucidate dynamic structural changes in proteins. She was a strong advocate of synchrotron radiation as a tool for structural biology, working to establish third generation synchrotrons. Her delight in science and kindness toward her colleagues and students were an inspiration to those who knew her.

Early life

Louise Johnson was born on 26 September 1940 in Worcester, the second of the three daughters of George Edmund Johnson (1904–1992), a former wool broker then serving in the RAF (in which he reached the rank of Wing Commander), and his wife Elizabeth Minna, née King (1914–1992). The family moved around the country following George Johnson’s RAF postings, from Exton to Market Harborough, and then to London in 1946. Louise attended Putney High School and then a school in Aberdeen, where the family lived for three years in the early 1950s, before moving to Wimbledon High School for Girls on their return to London. There she excelled, eventually becoming head girl. Her headmistress was an important inspiration to her. Both her school and family put a great value on girls’ education. Her mother had obtained a degree from University College London (UCL), and it was at the same institution that Louise studied for a BSc degree in physics, graduating in 1962.

PhD research on lysozyme at the Royal Institution

Later that year Louise started her PhD research at the Royal Institution, whose director was Lawrence Bragg FRS; Nobel Prize for Physics 1915). While Cavendish Professor at Cambridge, Bragg had overseen John Kendrew’s (FRS 1960) and Max Perutz’s (FRS 1954) crystallographic studies of myoglobin and haemoglobin that had revealed the first protein structures in the 1950s (for which they were awarded the Nobel Prize for Chemistry in 1962). By the 1960s, it was time to move on to enzymes.

Louise’s PhD project on an X-ray crystallographic study of N-acetylglucosamine (GlcNAc) and its relation to lysozyme was supervised by David C. Phillips (FRS 1967; later Lord Phillips of Ellesmere), whose research on lysozyme would describe the first atomic-resolution structure of an enzyme (figure 1). Lysozyme is the factor discovered by Alexander Fleming (FRS 1943) in nasal mucus responsible for dissolving certain bacteria (Nobel Prize for Physiology or Medicine 1945). Louise’s PhD studies would explain how the enzyme recognizes its substrate (an oligosaccharide component of the bacterial cell wall) and catalyses its hydrolytic cleavage at a specific site. For her first project, to understand the structure of a part of lysozyme’s oligosaccharide substrate, David Phillips gave Louise the task of determining the crystal structure of GlcNAc. This took two years (1261)*. Louise used visual estimation to measure the X-ray intensities recorded on photographic film, with the Royal Institution workshop producing a modification of the Weissenberg camera to simultaneously record intensities on the zero and higher levels of the reciprocal lattice, and wrote her own structure factor program (3). The crystal structure indicated that there was a mixture of α- and β-configuration sugars in the crystal lattice, a conclusion that she was able to substantiate with optical rotation measurements, and that was later found to occur with other sugars. Louise began work on inhibitor binding studies to lysozyme in 1964 by incubating lysozyme crystals with GlcNAc and other substrate analogues, and she used a novel approach of difference Fourier synthesis to determine how ligands interact with proteins. The resulting 6 Å resolution three-dimensional map obtained in October 1964 showed a peak of additional electron density located in the cleft separating the two domains of the molecule. This identified the catalytic site (2) (figure 2). This first difference electron density map for the lysozyme–inhibitor complex showed the power of the difference Fourier synthesis to locate a low-molecular-mass compound bound to a large protein molecule. During a special meeting at the Royal Institution in London in 1965, when David Phillips unveiled the three-dimensional atomic structure of lysozyme for the first time, Louise stunned the audience by describing how the enzyme bound these substrate analogues.

Figure 1.

Figure 1. The lysozyme team at the Royal Institution: G. A. Mair, C. C. F. Blake, Louise Johnson, A. C. North, D. C. Phillips, V. R. Sarma. (Photograph courtesy of A. C. North.) (Online version in colour.)

Figure 2.
Figure 2. A 6 Å resolution model of lysozyme. Hatched lines indicate the position of the increase in electron density observed in the presence of di-N-acetylchitobiose. (Reproduced from (2).)

 

She then progressed to determine the 2 Å resolution structure of lysozyme with the trisaccharides tri-GlcNAc and tri-N-acetylchitotriose. Lysozyme had been co-crystallized with tri-N-acetylchitotriose by John Rupley, a visiting scientist from Arizona University (45155). These structures revealed how the trisaccharide bound to three sites within the cleft (termed sub-sites A, B and C). On the basis of Louise’s structures, model building and carbohydrate chemistry, David Phillips deduced the first stereochemical description of an enzymatic mechanism, demonstrating the enormous explanatory power of protein crystallography and founding the field of structural enzymology. Louise was delighted; as she recalled in 1998: ‘On the 1st of February [1966] I was away from the Royal Institution at the US Embassy obtaining my immigration visa for a postdoctoral position in Fred Richards’ laboratory at Yale University. On the 2nd of February, 1966, I was back in the lab and my diary records “David has done it. Everything is explained beautifully. What a moment. Everybody rushed and excited.”’ (51). The mechanism was presented for the first time at a meeting at the Royal Society the following day (3 February 1966). The mechanism proposed cleavage between the MurNAc (N-acetyl muramic acid) and GlcNAc (N-acetyl-glucosamine) moieties bound to sub-sites D and E, respectively. The sugar moiety in sub-site D is distorted from a chair to sofa geometry, reminiscent of the transition-state carbonium ion intermediate. Formation of this intermediate is promoted by Glu35 acting as a general acid to protonate the glycosidic oxygen. The resultant positively charged carbonium ion is stabilized by Asp52. Glu35 next functions as a general base to deprotonate a nucleophilic water molecule to generate the product. The proposed catalytic mechanism was a landmark achievement. It contained suggestions for essentially every structural contribution to the catalytic power of enzymes that has since been identified: proximity, ground-state distortion, alteration of catalytic-group pKa by the unique environment of the enzyme, general acid–base catalysis, and transition-state stabilization by electrostatic and hydrogen-bonding interactions. As Max Perutz commented in his closing remarks of the meeting, ‘For the first time we have been able to interpret the catalytic activity of an enzyme in stereochemical terms’ (51).

In 2008, reflecting on her postgraduate experience, Louise recalled that ‘the first year of graduate research was hard, especially coming from a physics background where the subject was based on definite knowledge. When experiments did not work, I would envy the girls who worked at the Harrods department store, which I used to pass each day on my bus journey to work. They knew what they had to do and could go home in the evening and forget about work. However, once an experiment started to work and I felt that I had discovered something new that no one else knew, the effect of research was addictive. It was the small triumphs and the acquisition of new skills that hooked me to a life in research’ (61).

Postdoctoral research on ribonuclease at Yale University

Later in 1966 Louise moved to the Department of Biophysics at Yale University, New Haven, USA, for postdoctoral research in the group of Frederic Richards and Hal Wyckoff. There, she contributed to the structure determination of the enzyme ribonuclease (RNase) S (56). She wrote a program to compute the phases using the David Blow (FRS 1972) and Francis Crick FRS probability weighting system, which, by accounting for errors in observations, generates the best electron density map. In an independent collaboration with Richard Perham (FRS 1984), she irradiated ribonuclease with neutrons generated at the Brookhaven Graphite Research Reactor to identify the platinum-binding site on the enzyme.

Oxford

Louise returned to the UK in 1967 to join the newly established Laboratory of Molecular Biophysics at the University of Oxford. She was to spend the next 44 years in Oxford, ‘with great contentment’ (61).

The Laboratory of Molecular Biophysics, housed in the Department of Zoology, was headed by David Phillips, who had moved his lysozyme team there from the Royal Institution following the retirement of Lawrence Bragg. The head of the department, John Pringle FRS, had a remarkable vision of integrating biology from molecule to animal. Louise was initially appointed as the departmental demonstrator, the lowest rung on the academic career, but would retire from the University of Oxford 40 years later as the David Phillips professor of molecular biophysics, and professorial fellow of Corpus Christi College. Dorothy Hodgkin FRS; Nobel Prize for Chemistry 1964) introduced Louise to Somerville College in 1967, where Louise was appointed as the first Janet Vaughan Lecturer and Fellow, an appointment enabled by a donation from Dorothy Hodgkin (Adams 1996), and later as an honorary fellow in 1990 (41). Somerville College had been established in 1879 to provide education to women in Oxford. Its provision of childcare facilities to working mothers, well ahead of the times, offered crucial support to Hodgkin and Louise to help tackle their competing tasks of raising families, research and teaching.

The university block grant allocation system in the late 1960s allowed Louise considerable freedom to explore new projects without the requirement to apply for grant funding. Among the early projects she investigated were crystallographic analysis of triosephosphate isomerase and aldolase. The study of these two glycolytic enzymes was part of a coordinated effort to undertake a comparative evolutionary analysis of the structure and mechanism of all enzymes of the glycolytic pathway, an idea championed by Phillips and involving research groups in Oxford, Cambridge, Bristol and Purdue. These studies revealed that enzymes of the glycolytic pathway shared domains of similar architecture. Louise developed an interest in electron microscopy (EM), taking charge of the EM unit in the department. She used EM to study protein crystals and adrenalin storage chromaffin granules (10).

Formation of the Oxford Enzyme Group in 1969, comprising protein crystallographers Johnson and Phillips, nuclear magnetic resonance (NMR) spectroscopist Rex Richards FRS, organic chemist Gordon Lowe (FRS 1984) and enzymologist Jeremy Knowles (FRS 1977), and involving fortnightly dinner meetings at one of the colleges, fostered a powerful and flourishing interdisciplinary research environment in Oxford.

Glycogen phosphorylase

In 1971 Louise initiated research on glycogen phosphorylase, a study that was to dominate her research activities for over two decades and that would lead to far-reaching and fundamental insights into mechanisms of enzyme regulation by protein phosphorylation and allosteric effectors. Glycogen phosphorylase regulates entry into glycolysis by catalysing the breakdown of the storage molecule glycogen (in muscle and liver) to glucose-1-phosphate (G1P) for ATP generation. In many respects this reaction resembles the hydrolysis of the MurNAc-GlcNAc polysaccharide of bacterial cell walls catalysed by lysozyme, which Louise had studied for her PhD. However, glycogen phosphorylase is a hugely more complicated enzyme in terms of its size (25 times larger than lysozyme) and its catalytic mechanism and intricate regulatory mechanisms. Glycogen phosphorylase had been discovered by Carl Cori (ForMemRS 1950) and Gerty Cori in the 1930s (Cori & Cori 1940; Nobel Prize for Physiology or Medicine 1947); they had shown that the enzyme was under metabolic regulation. High cellular concentrations of adenosine monophosphate (AMP), produced by adenosine triphosphate (ATP) hydrolysis (thus denoting low energy status), activates glycogen phosphorylase to increase flux through the glycolytic pathway to replenish ATP levels. In contrast to the activation of glycogen phosphorylase, under low cellular energy conditions, high concentrations of glucose and glucose-6-phosphate (G6P) (starting metabolites for glycolysis) and ATP inhibit glycogen phosphorylase activity. Detailed enzymology by the Coris and others showed that glycogen phosphorylase bound its activator AMP (an effector) through positive homotropic cooperativity with a Hill coefficient of 2 (Cori et al. 1943Helmreich & Cori 1964). The substrate inorganic phosphate is also bound cooperatively, whereas AMP and phosphate mutually assist their binding (an example of positive heterotypic cooperativity). These studies on phosphorylase provided much of the supporting data for the concerted theory of allostery proposed by Monod (ForMemRS 1968), Wyman and Changeux (MWC) (Monod et al. 1965). In this model, the equilibrium describing the interconversion of active (R) and inactive (T) states of an allosteric protein is modulated by allosteric effectors. In the instance of phosphorylase, AMP (an activator) shifts the equilibrium to the R state, whereas glucose, G6P and ATP (inhibitors) shift the equilibrium to the T state.

Glycogen phosphorylase is also renowned for being the first protein recognized to be regulated by reversible protein phosphorylation, a process that controls the interconversion of phosphorylase between the GPa and GPb states. Eddy Fischer (ForMemRS 2010) and Ed Krebs’s discovery in 1955 (Fischer & Krebs 1955; Nobel Prize for Physiology or Medicine 1992) was the first step in understanding the highly diverse mechanisms of post-translational modifications that underlie regulation of all biological processes. Glycogen phosphorylase is converted into the active GPa state (without requiring AMP for stimulation) by phosphorylation of a single serine residue (Ser14) by phosphorylase kinase. Phosphorylase kinase is itself activated directly by Ca2+ (in muscle; which also stimulates muscle contraction that utilizes ATP) and also by phosphorylation by another protein kinase (PK): PKA. PKA is activated by cAMP, a second messenger generated in tissues in response to the fright and flight hormone adrenalin. A protein phosphatase (PP1) dephosphorylates GPa.

How glycogen phosphorylase recognizes and integrates these diverse signals to regulate its enzymatic activity presented a fascinating system for study by structural biology. David Phillips, who had visited Fischer and Krebs in Seattle, introduced Louise to glycogen phosphorylase with a portfolio of their papers. The first crystals of glycogen phosphorylase were provided by Neil Madsen of Edmonton, Canada. The project had been offered to Mike James (FRS 1989) in Edmonton, who was just establishing his group around that time, but Mike suggested Neil pass the project on to Louise. The large unit cell dimensions (119, 190, 88 Å) of these monoclinic crystals (space group P21) with one tetramer of phosphorylase (400 kDa) per asymmetric unit, and weak diffraction from in-house rotating anode X-ray sources, represented a formidable challenge to the then available methods of protein crystallography. By a stroke of good fortune, Louise’s team discovered a new crystal form of phosphorylase (7). Phosphorylase purified with the help of the Oxford Enzyme Group’s Enzyme Preparation Laboratory yielded crystals that appeared overnight, without a conventional precipitant, in a solution containing AMP and magnesium chloride. These new tetragonal crystals diffracted strongly in-house, and, owing to their high symmetry and smaller asymmetric unit (comprising one 842-residue subunit), although still a massive challenge, were more amenable to structure determination. An initial hurdle, difficulties in reproducing these crystals, was solved when Neil Madsen, who visited Oxford, discovered that the original crystallization solution contained inosine phosphate (IMP), converted from AMP owing to contaminating AMP deaminase in the phosphorylase preparation. IMP is a weak allosteric activator, which alone does not induce the R state, so the early structural studies on phosphorylase were on the inactive unphosphorylated T state.

Phosphorylase structure and catalytic mechanism

Louise, with her student Keith Wilson and others in the phosphorylase group, published the first 6 Å resolution structure of T state phosphorylase b in 1974 (9), followed by a 3 Å structure four years later, with Irene Weber and John Jenkins having later joined the group (1213) (figure 3). Studies to identify ligand-binding sites for substrates and allosteric effectors were performed using the difference Fourier approach Louise had pioneered for identifying substrate binding to lysozyme (1415). In the 1970s glycogen phosphorylase was the largest protein structure determined. Interpretation of the electron density map was made possible by the complete amino acid sequence of the 842-residue phosphorylase molecule recently obtained at the University of Washington in Seattle (Titani et al. 1977). A molecular model of phosphorylase on the scale of 2 cm−1Å, built using a Richards Box, occupied a whole room in the zoology department basement (figure 4). To help build an accurate model, John Marsh, of the Laboratory of Molecular Biophysics workshop, developed a new sound ranging coordinate-measuring device. Model building proved enormously instructive (although laborious) and facilitated interpretation of the structure. Refinement of the coordinates, performed using constrained least-squares refinement methods (Konnert 1976), was performed using the Science Research Council’s Cray-1 supercomputer at Daresbury (16). Today the same calculations would take a few minutes on a desktop computer.

Figure 3.
Figure 3. Zoology department, University of Oxford, 1976. Front row: Louise Johnson (third from left), D. C. Phillips (centre), John Pringle (left of D. C. Phillips). Second row: K. Wilson (seventh from left), Irene Weber (sixth from right). (Photograph courtesy of Keith Wilson.) (Online version in colour.)
Figure 4.
Figure 4. Wire model of T state glycogen phosphorylase b, early 1980s. (Photograph courtesy of Janos Hajdu.) (Online version in colour.)

 

The two subunits of the functionally active phosphorylase dimer are related by the crystallographic two-fold axis. Each subunit is composed of two domains of roughly equal size, with the N-terminal domain including the glycogen storage sub-domain. The C-terminal domain forms a dinucleotide-binding domain, common to some other glycolytic enzymes. The sites for the allosteric activator AMP, and allosteric inhibitors G6P and ATP are located at the subunit interface, separated from the catalytic site by 40 Å. The subunit interface of the functional dimer is composed of two large projections, known as the ‘cap’ and ‘tower’, which make extensive contacts with the other subunit. In the Weber paper of 1978 (13), Louise and colleages identifed the position of the essential cofactor pyridoxal 5′-phosphate (PLP) (derived from the vitamin B6) and discovered that the substrate G1P bound in close proximity to the cofactor such that the phosphates of PLP and G1P were within 8 Å. This identified the catalytic site and provided the first clues that the phosphate group of PLP may play a direct role (rather than an indirect structural role) in catalysis. The catalytic site is located deep below the enzyme’s surface at the interface of the two domains, with limited access to the surface.

To obtain atomic detail, higher resolution was required. However, owing to the large size of the protein, phosphorylase crystals diffracted weakly on the in-house Elliot GX6 rotating anode X-ray generator. The breakthrough realization that a high-resolution structure could be achieved using the intense X-rays generated from synchrotron radiation sources was made in 1978 when Louise’s graduate student, Enrico Stura, visited Roger Fourme’s beam line at the LURE synchrotron near Paris. The 2 Å resolution diffraction pattern recorded on photographic film was ‘heart-stopping’ (3), and convinced Louise that synchrotron radiation was the key to solving the hardest problems in structural biology. Building on the work of Keith Wilson, who had collected data at LURE and at the PX7.2 station at Daresbury Synchrotron Radiation Source (SRS) (18), by the late 1980s David Stuart (FRS 1996) and Ravi Acharya used data they collected at the Daresbury beamline PX9.6 to determine a 1.9 Å resolution structure of T state phosphorylase b (33). The shorter wavelength of X-rays produced by the superconducting wiggler magnet at the PX9.6 beam line (1.003 Å) offered several advantages: crystal absorption, air absorption and scatter were reduced three-fold, improving signal to noise; the volume of the blind region was reduced; and the smaller scattering angles allowed all data to be collected on standard flat plate films. A detailed description of the overall structure, including analysis of secondary structure, hydrogen-bond networks and water molecules, ran to 120 pages published in a specially commissioned monograph (33).

The enzymatic mechanism of phosphorylase remained mysterious for some time before being elucidated through a combination of protein crystallography, biochemistry and inventive substrate analogues. The reaction mechanism proceeds with retention of configuration of the α(1–4)-linked glycosidic bond, similar to lysozyme; however, phosphorylase requires the PLP cofactor to catalyse the reaction between glycogen and inorganic phosphate. Unlike other PLP-dependent enzymes, which utilize the Schiff base formed between the PLP and the side chain of an enzyme lysine residue, a critical set of biochemical and NMR experiments indicated that the PLP cofactor used a different mechanism in phosphorylase involving the reversible anion–dianion transition of its phosphate group (Helmreich & Klein 1980Helmreich et al. 1982). Crystal structures of phosphorylase with the product G1P had already revealed the catalytic site close to the PLP phosphate group and a catalytically crucial arginine residue (Arg569) (13); however, these structures did not reveal either the function of the PLP phosphate group or how phosphorylase recognizes its glycogen substrate. Powerful insights into the catalytic mechanism were obtained from Ernst Helmriech at the University of Würzburg. Helmreich’s group had developed the glycosidic analogue heptenitol, which is phosphorylated in a reaction catalysed by phosphorylase, in a process mimicking the glycogen phosphorolysis reaction (Klein et al. 1984a,b). The product heptulose-2-phosphate is a potent inhibitor. Importantly, because the geometry of the phosphate in heptulose-2-phosphate is restrained by the methyl phosphate in the β-configuration, heptulose-2-phosphate acts as a transition-state analogue. This reaction was an attractive system for study in the crystal because it did not require an oligosaccharide substrate that cannot be accommodated at the catalytic site of T state phosphorylase crystals.

Louise’s PhD student, Paul McLaughlin, determined a structure of phosphorylase in complex with heptulose-2-phosphate, generated in the crystal from the substrates heptenitol and phosphate. Data for the phosphorylase–heptulose-2-phosphate complex were collected at the PX7.2 station, Daresbury SRS (20). The structure showed the phosphate moiety of heptulose-2-phosphate forming hydrogen bonds with the PLP phosphate, stabilized by the guanidinium group of Arg569. From this structure, Louise proposed a novel reaction mechanism in which the PLP phosphate functions to activate the substrate in a proton relay-acid/base catalytic mechanism. In the direction of phosphorolysis, the PLP phosphate first donates a proton to the substrate phosphate, which in turn acts as a general acid to protonate the leaving glycosidic oxygen, catalysing cleavage of the glycosidic bond. The resultant carbonium ion intermediate undergoes nucleophilic attack by the substrate phosphate, activated through proton withdrawal by the PLP phosphate group acting as a general base catalyst. This reaction yields G1P with retention of configuration. The close proximity of the two phosphates is stabilized by Arg569, which shifts from a site buried in the protein to a position where it can make contact with the product phosphate. There is a mutual interchange in position between the arginine and an acidic group, Asp283 of the 280s loop, a loop that blocks glycogen access to the catalytic site. These movements represent the first stage of the allosteric response that converts the catalytic site from a low- to a high-affinity phosphate and glycogen-binding site (202938). Phosphorylase represents the only known example of the PLP phosphate group participating in acid–base catalysis. The PLP-dependent phosphorolysis reaction mechanism appears to have evolved only once for a single biological purpose.

From careful analysis of the orientation of lone pair orbitals of oxygen atoms in the O(5)-C(1) and C(1)-O(1) bonds of heptenitol, Louise deduced that the conformation of heptulose-2-phosphate at the catalytic site was significant because it is similar to that predicted from stereoelectronic arguments to weaken the exo-anomeric effect, resulting in increased polarization of the C(1)-O(1) bond. As a consequence, this would promote cleavage of the α-glycosidic bond. The preferred conformations for α-glycosides are to strengthen the glycosidic bond. For G1P it was anticipated that the presence of oligosaccharide at the catalytic site would favour a conformation in which the phosphate adopts a conformation to weaken the exo-anomeric effect, therefore promoting catalysis (2324). This was a remarkable feat of deductive reasoning.

Time-resolved crystallography

The capacity of the T state tetragonal crystals to catalyse the reaction of oligosaccharide and heptenitol with phosphate in situ, generating their products, inspired projects led by the enzymologist Janos Hajdu, a visiting scientist from Budapest, in time-resolved studies to follow the reaction process at the catalytic site of phosphorylase using protein crystallography. Direct observation of the progress of a catalysed reaction in crystals of glycogen phosphorylase b was made possible through fast crystallographic data collection achieved at the SRS at Daresbury (212427).

Crystals of glycogen phosphorylase are capable of slowly transforming the glycosylic substrate analogue heptenitol into the product heptulose-2-phosphate in the presence of phosphate. The rate-limiting step in this reaction is the interconversion of the ternary enzyme–substrate complex into the product. As a consequence, the active enzyme–substrate complex should transiently accumulate in the crystal. Hence, providing that reaction initiation and data collection are fast relative to the turnover rate of the catalytic reaction in the crystal, it should be possible to observe the ternary enzyme–substrate complex before it is converted to the product, heptulose-2-phosphate. In the first time-resolved diffraction experiments at the synchrotron, the control properties of the enzyme were also exploited to further slow the reaction by nearly 500 times relative to solution rates, and a turnover took about five hours (21).

The crystal was mounted in a flow cell and the reaction was initiated by flowing substrates over the crystal. Diffusion of the substrate and half-saturation binding took less than 10 minutes (27). Data collection took place either immediately after the introduction of the substrates or after various resting times to allow the reaction to proceed. Changes in electron density in the difference Fourier maps were observed as the reaction proceeded. The results were interpreted as depicting the formation and transformation of the ternary enzyme–substrate complex into the product heptulose 2-phosphate (21).

Time-resolved diffraction studies on faster reactions require faster reaction initiation and faster data collection. These problems were resolved by two innovations: inert (caged) substrates that could be liberated by photolysis in situ, synchronizing every enzyme molecule in the crystal; and Laue diffraction using the bright broad spectrum of X-rays emitted by synchrotron radiation sources which simultaneously satisfy Laue diffraction conditions without rotating the crystal (2224). In theory, the intense radiation offered by synchrotron radiation would require short, millisecond exposure times, allowing a series of exposures to be collected in rapid succession once the reaction had been initiated by flash photolysis of the caged substrate. Hajdu and Louise, along with Mike Elder, Pauline Machin, Trevor Greenough and others, calculated the first electron density map using Laue diffraction from a protein crystal on the millisecond time-scale (24). However, these approaches, while technically pioneering, were challenging to apply to investigate mechanisms of phosphorylase catalysis; one reason being that the tetragonal T state crystals did not allow the full interconversion to the active (R state) conformation at the catalytic site, preventing oligosaccharide engagement. However, these approaches, although not without their limitations because of spatial and harmonic overlaps, were exploited in other systems, particularly light-dependent reactions and small GTPases, providing important insights into catalytic mechanisms (28).

Allosteric mechanism and control by protein phosphorylation

Phosphorylation of GPb triggers a change to a state (GPa) with high catalytic activity and intrinsic affinity for AMP. Although AMP is not required for GPa activity, AMP augments activity by 10%. Both phosphorylation of GPb and the binding of AMP to GPb trigger changes at the catalytic site to promote phosphate and glycogen binding. Biochemical data showed that activation is associated with a transition of the pyridoxal phosphate from the inactive monoanion to the active dianion (Helmreich & Klein 1980). Thus, metabolic effectors and protein phosphorylation modulate the equilibrium between two conformational states of phosphorylase: the inactive T state and the active R state, conforming to the MWC concerted model of allosteric proteins (Monod et al. 1965). Insights into the question of conformational changes promoted by phosphorylation and binding of metabolites were provided by ligand binding studies to the T state GPb crystals. These studies revealed that the AMP allosteric site is located at the dimer interface, allowing AMP to contact both subunits of the dimer. The catalytic site, on the other hand, is buried at the centre of the molecule 15 Å below the molecular surface and separated from the allosteric site by 30 Å. Soaking AMP into GPb tetragonal crystals did not induce a conformational change of phosphorylase to explain how AMP binding at the allosteric site communicates to both catalytic sites and the second allosteric site.

Allosteric inhibitors also control phosphorylase activity. Louise’s research showed that the inhibitors ATP and G6P bind to the same allosteric site as AMP, competing for AMP binding and also forming a different set of contacts at the dimer interface to stabilize the T state (15171940). Robert Fletterick’s group, working with Neil Madsen and Louise on GPa crystallization (Fletterick et al. 1976a), had determined the structure of glycogen phosphorylase a in the presence of glucose (Fletterick et al. 1976b). Glucose induces the inactive T state and the GPa–glucose complex crystallized in the same tetragonal space group as GPb with IMP, meaning that, in the presence of glucose, phosphorylation of Ser14 (pSer14) was uncoupled from a complete allosteric response of the whole enzyme. A comparative study of GPa and GPb in these crystal forms showed that phosphorylation of Ser14 induced a large conformational change of the flexible N-terminal segment (N-terminal 22 residues) to form inter-subunit contacts in GPa (25), a finding that extended earlier proposals from lower-resolution structures (13). This was correlated with a disordering of the extreme C-terminal five residues. The pSer14 group forms electrostatic interactions with a pair of Arg residues, one from each subunit of the dimer. Inter-subunit contacts are augmented by residues immediately flanking pSer14, indicating specificity for the sequence context of the pSer14 group. In GPb, the N-terminal segment is extended and mobile. Jennifer Martin observed that the poorly ordered N-terminal residues of GPb formed intra-subunit interactions with the Ser14 hydroxyl group in close proximity to the carboxylate of Glu501 (32). Phosphorylation of Ser14 therefore destabilizes the T state conformation of the N-terminal tail, while stabilizing the R state conformation.

Comparison of the GPa and GPb structures suggested possible routes of communication between the allosteric and catalytic sites, but did not reveal mechanisms. Although phosphorylation induced conformational changes of the N-terminal segment and small tertiary changes of the cap region, there was only a small change of quaternary structure and no change at the catalytic site. Lattice contacts in the tetragonal crystal prevented a full conformational response to allosteric effectors and Ser14 phosphorylation. Since the conformational transition of T state to R state phosphorylase could not be accommodated within the tetragonal crystal form, David Barford (FRS 2006), a PhD student in Louise’s group, returned to the monoclinic crystal form of phosphorylase originally described by Madsen (1972), now more tractable owing to the intense X-rays available at synchrotron radiation sources. These crystals were grown from 1 M ammonium sulfate (an activator) with and without AMP, and since GPa and GPb crystals were isomorphous, represented the R state conformation of phosphorylase. The structure of R state phosphorylase b published in 1989 (26), followed two years later as a complex with AMP together with R state phosphorylase a (3436), revealed the full allosteric response induced by non-covalent allosteric effectors and protein phosphorylation (figure 5). Protein phosphorylation and ligation of the allosteric effector AMP promote essentially the same conformational change by virtue of stabilizing the R state. True to the MWC model of concerted allosteric proteins (Monod et al. 1965), this conversion involves a change in orientation of the two subunits of the dimer. The conservation of two-fold symmetry means that both subunits change in a concerted manner, and the coupling of tertiary and quaternary structure is the key to understanding the communication of conformational changes between remote sites on the enzyme. The optimal binding of the non-covalent effector AMP and the covalent effector pSer14 to sites located at the dimer interface causes a tightening of inter-subunit contacts on one side of the interface. The resultant quaternary conformational change pulls the two subunits apart at the opposite side of the dimer interface, weakening these inter-subunit interactions. At this interface, the relative packing angle of interlocking α-helices (the tower helices) switches by 60°. This new packing angle accommodates a combined change of tertiary and quaternary structure. A tertiary conformational change of the tower helices, which are directly linked to the 280s loop blocking the catalytic site, disorders the 280s loop, removing an obstacle to glycogen binding (23) and allowing Arg569 to replace Asp283. These localized conformational changes create a binding site for the inorganic phosphate substrate, and promote the anion to dianion conversion of the PLP phosphate.

Figure 5.
Figure 5. Comparison of R state glycogen phosphorylase a (left) and T state glycogen phosphorylase b (right) dimers. Two views are shown. Phosphorylation of Ser14 at the N-terminus restructures the N-terminal tail and causes interdependent quaternary and tertiary conformational changes that stimulate the catalytic activity of the enzyme. (From (34), used with permission from Elsevier.) (Online version in colour.)

 

Louise’s study of glycogen phosphorylase (30) provided the first stereochemical explanation for the control of an enzymic activity by allosteric effectors, and the second for any protein, following Max Perutz’s work on haemoglobin (Perutz 1989). It was the first time that the regulatory mechanism of protein phosphorylation was understood at a molecular level. Protein phosphorylation regulates nearly all intracellular proteins. Louise’s studies on phosphorylase provide a framework for understanding how these systems operate. The phosphorylase study anticipated the tremendous capacity of a reversibly attached phosphate group to mediate diverse structural changes of proteins and multiprotein complexes, rationalizing why phosphorylation is involved in virtually every regulated biological process. In recognition of her scientific achievements, in 2009 the Biochemical Society awarded Louise the Novartis Prize and Medal, its most prestigious award. In her Medal lecture, Louise delineated the structural basis of phosphoregulation of diverse biological processes discovered in the intervening 20 years (63). These in essence share common features first seen with phosphorylase: modulation of protein–protein interactions, coupled to protein conformational changes. Additionally, in phosphorylase, the rotation of the tower α-helices that accompanies the quaternary conformational change caused by AMP binding and phosphorylation, and is responsible for communicating the allosteric response between catalytic sites, was a foretaste of the conformational changes underlying transmembrane signalling mediated by cell-surface receptors and G protein-coupled receptors.

By the early 1990s, Louise’s research had addressed the key fundamental questions relating to mechanisms of phosphorylase catalysis and regulation. However, an important unresolved question was the mechanism of oligosaccharide recognition at the catalytic site. The answer to this long-standing question was finally answered when Louise turned to study the maltodextrin phosphorylase from Escherichia coli, closely related to mammalian glycogen phosphorylase but lacking regulatory control mechanisms. In collaboration with Dieter Palm from Würzburg, in the late 1990s Kim Watson determined the structure of E. coli maltodextrin phosphorylase as a ternary complex with thio-oligosaccharide and phosphate (4954). The results demonstrated the arrangement of the inorganic phosphate substrate, hydrogen-bonded to the 5′-phosphate of the cofactor and in a position to act as a general acid to promote cleavage of the glycosidic bond. As predicted from model building, the oligosaccharide had an unusual torsion angle between the two terminal sugars that facilitated the catalytic reaction and allowed the reaction to proceed with retention of configuration.

Glycogen phosphorylase as a drug target for diabetes

Insights gained into phosphorylase structure and function and mechanisms of allosteric control had practical implications for developing new therapies for treating human disease. Type-2 diabetes, characterized by elevated blood glucose levels, affects 2% of the population. Liver glycogen phosphorylase is a potential target for drugs that control blood glucose concentrations. Compounds that stabilize T state GPa could function to promote glucogenesis, reducing blood glucose levels and acting as diabetic drugs.

Based on discussions with Peter Goodford, who suggested that phosphorylase might be a viable drug target for treating diabetes, in a series of studies Louise, with her students Jennifer Martin and Kim Watson and others, explored the structure–function relationship of novel T state GPa inhibitors. Some of these had efficacy in cells (354245505657). Interestingly, these studies led to the unexpected discovery of a novel allosteric-binding site located at the tower helix subunit interface (57).

Election to the David Phillips chair and research on protein kinases

The year 1990 was pivotal for Louise. She was elected a Fellow of the Royal Society and was appointed as the David Phillips Professor of Molecular Biophysics. The chair, generously endowed for perpetuity by the EP Abraham Trust, is associated with a professorial fellowship at Corpus Christi College. Because of her scientific stature and reputation, Louise was the natural successor of David Phillips (figure 6). She had already acted as his deputy since 1984, and overseen the relocation of the Laboratory of Molecular Biophysics to purpose-built laboratory space in the new Rex Richards Building in late 1984, a move accompanied by the Laboratory of Molecular Biophysics becoming a sub-department of the Department of Biochemistry. Dorothy Hodgkin, who had encouraged David Phillips to move his team to Oxford in 1967, was one of the first to congratulate Louise on her election to the David Phillips professorship (Ferry 2019) (figure 7). The year 1990 also marked a redirection of Louise’s research efforts away from glycogen phosphorylase towards the wider question of the molecular mechanisms underlying cellular regulation by reversible protein phosphorylation, with a particular emphasis on control of the cell cycle. As head of the Laboratory of Molecular Biophysics, Louise directed the laboratory’s research efforts into new areas of molecular structural biology. In addition, the lab moved away from classical approaches of isolating proteins from natural endogenous sources and adopted more modern molecular biology approaches, such as recombinant gene expression from E. coli and baculovirus/insect cells. This was crucial for facilitating structural investigations of multi-domain proteins and multi-subunit complexes, and to vigorously test and validate molecular hypotheses through site-directed mutagenesis (37).

Figure 6.
Figure 6. David Phillips and Louise Johnson at the Ciba Foundation in 1991 (with Ben Bax in the background.) (Photograph copyright unknown.)
Figure 7.
Figure 7. Chatting with Dorothy Hodgkin shortly after Louise’s election as a Fellow of the Royal Society and to the David Phillips professorship of molecular biophysics, 1990. (Photograph copyright Norman McBeath.)

 

For many years after its discovery, the regulation of biological processes by reversible protein phosphorylation was thought to be confined to glycogen metabolism. Today, phosphorylation is recognized as being the major mechanism for regulating biological processes, from the control of the cell cycle to the immune system, muscle contraction, responses to hormonal and extracellular signalling, and learning and memory processes. Dysfunctional protein phosphorylation underlies numerous diseases, including cancer and auto-immune conditions. The enzyme that phosphorylates glycogen phosphorylase, phosphorylase kinase, was the first protein kinase discovered (Fischer & Krebs 1955Krebs & Fischer 1955). It is the founding member of a family of over 500 protein kinases responsible for phosphorylating at least one-third of all intracellular proteins. The protein tyrosine kinase Src was the first discovered oncogene (Peyton Rous (ForMemRS 1940), Nobel Prize for Physiology or Medicine 1966; Harold Varmus and Michael Bishop (ForMemRS 2008), Nobel Prize for Physiology or Medicine 1989), and many anti-cancer drugs target protein kinases whose aberrant activation is responsible for oncogenesis (59).

Having elucidated mechanisms of glycogen phosphorylase catalysis and regulation in the 1980s, Louise initiated research programmes on the protein kinases. Important aims were to understand their mechanisms of regulation and how they specifically select their target for phosphorylation. Initial efforts focused on the phosphorylase kinase catalytic domain, a component of the 16-subunit holoenzyme ((α,β,γ,δ)4 stoichiometry, 1.3 MDa). As a first step towards understanding the structure and function relationships of this complex enzyme, Louise, with her student David Owen (FRS 2017) and postdoc colleague Ed Lowe, determined the crystal structure of the kinase domain (residues 1–298) of the catalytic γ-subunit of phosphorylase kinase in complex with a non-hydrolysable substrate ATP analogue and peptide substrate (4448). This was the first structure of a serine/threonine protein kinase in complex with a peptide substrate, published within a few weeks of Steve Hubbard’s structure of the protein tyrosine kinase domain of the insulin receptor in complex with a tyrosine-containing peptide (Hubbard 1997). Phosphorylase kinase is a remarkably specific protein kinase. It recognizes a single serine residue in phosphorylase (Ser14, one of 29 in the 842-residue subunit). Moreover, unlike most other protein kinases, phosphorylase kinase is specific to glycogen phosphorylase. A peptide modelled on the N-terminal segment of phosphorylase incorporating Ser14 is a poor substrate of phosphorylase kinase. Peptide substrates exhibit Km values that are ca 50-fold higher than the corresponding Km values for phosphorylase itself (Graves 1983), suggesting that structural features of the phosphorylase molecule may play a role in recognition. To overcome the problems of the low-affinity peptide, Louise’s group used a modified peptide shown in an orientated degenerate peptide array to have an enhanced affinity for phosphorylase kinase (48). The substrate peptide was found to form a short anti-parallel β-sheet with the kinase activation segment, the region that plays an important role in regulating enzyme activity in protein kinases. This anchoring of the main chain of the substrate peptide at a fixed distance from the γ-phosphate of ATP explained the selectivity of phosphorylase kinase for serine/threonine over tyrosine as a substrate. The structure also provided further insights into the catalytic mechanisms of protein kinases, complementing those obtained by Susan Taylor and colleagues from the structure of the catalytic subunit of PKA in complex with its peptide inhibitor PKI (Knighton et al. 1991a,b).

In 1996 Louise published an influential review that, based on a comparison of inactive and active protein kinase structures, defined the regulatory role of the activation segment in determining the relative orientation of the N- and C-terminal domains, and in modulating the catalytic site conformation (46). Importantly, the phosphorylase kinase study (48) extended these observations through the discovery that the extensive interactions between the activation segment and a peptide substrate revealed another mechanism by which the conformation of this segment can influence kinase activity. This provided a further explanation why residues of the activation segment are frequently responsible for control by reversible phosphorylation.

The huge size of the phosphorylase kinase holo enzyme (1.3 MDa) was another immense challenge to the techniques of structural biology, although today the structure determination of such large complexes by cryo-EM is almost routine. Louise was early to appreciate the value of single particle EM for determining protein structures; in the early 2000s she installed an EM facility in the basement of the Rex Richards Building with a refurbished 100 keV microscope acquired from the zoology department. This was over a decade before the resolution revolution in cryo-EM made it the method of choice for structural biologists. In 2009, in one of her last research papers, Louise, with the electron microscopist Catherine Venien-Bryan and colleagues, reported the 9.9 Å resolution cryo-EM structure of phosphorylase kinase (64). The cryo-EM study revealed an elegant butterfly-shaped structure measuring 270 Å. The catalytic γ-subunits are located at the four peripheral tips of the molecule, which the team decorated with its 200 kDa substrate, glycogen phosphorylase. In their model, only one GPb monomer from the dimer is firmly bound to phosphorylase kinase. GPb recognition by phosphorylase kinase would involve not only the local epitope around Ser14 but also other regions of GPb, thus explaining the 50-fold increased affinity of phosphorylase kinase for GPb relative to peptide substrates.

Studies of cell cycle protein kinases

Concurrent with her efforts on phosphorylase kinase, Louise opened up new areas of research, investigating molecular mechanisms of cell cycle control. Discoveries made by Tim Hunt (FRS 1991), Paul Nurse (FRS 1989), Lee Hartwell (Nobel Prize for Physiology or Medicine 2001) and others had revealed that cell cycle oscillations are controlled by cyclin-dependent kinases (CDKs). CDKs phosphorylate a range of substrates to control cell cycle transitions such as mitosis and chromosome replication. How these kinases are themselves regulated and how the different kinase–cyclin pairs select their substrates in a cell cycle-dependent manner were areas of intense interest.

From the 1990s onwards, Louise was to devote most of her research efforts to addressing these questions. CDKs are activated both by the binding of cyclins (whose amounts oscillate during the cell cycle) and by phosphorylation of a conserved activation segment threonine residue. Conversely, CDKs are inhibited by CDK inhibitors. Research on CDKs was stimulated through discussions with Paul Nurse, who had been appointed as the Iveagh Professor of Microbiology at the Department of Biochemistry in Oxford in 1987. Nurse, with his postdoc Kathleen Gould, had made the intriguing discovery in 1989 that phosphorylation of the CDK residue Tyr15, close to the putative ATP-binding site, inhibited CDK activity (Gould & Nurse 1989). Such a direct role of phosphorylation in controlling substrate binding clearly differed from the allosteric mechanism operating in glycogen phosphorylase (2634).

During the 1990s Tim Hunt, with whom Louise and colleagues had established a productive collaboration, enlivened these investigations with his frequent visits to Louise’s lab. In 1995 Louise, with her cell cycle team of Nick Brown, Jane Endicott, Martin Noble and others, including Tim Hunt and Elspeth Garman, determined the crystal structure of cyclin A—providing a long-awaited answer to the question of the cyclin box architecture, shown to form an α-helical fold of five α-helices, a fold that is repeated in the C-terminus of the protein (43). This study, together with the crystal structure of the CDK2–cyclin A complex from the group of Nicola Pavletich (Jeffrey et al. 1995), explained how cyclins promote CDK activation. Cyclins are rigid structures. On binding to the inactive CDK, the cyclin subunit induces a conformational change of the kinase αC helix and activation segment to realign catalytic residues for productive binding of ATP. However, the full activation response also requires phosphorylation of a conserved activation segment Thr residue (Russo et al. 1996). To answer the question of how CDK–cyclin complexes bind substrates and inhibitors, Louise’s cell cycle team determined the structures of phosphorylated CDK2–cyclin A as complexes with both peptide substrates and the cyclin A recruitment RxL motif-containing peptide (52). CDKs selectively phosphorylate Ser and Thr residues with C-terminal Pro and basic residues at positions P+1 and P+3, respectively. Their paper (52) indicated how the substrate peptide-binding site of CDK2 forms a pocket that complements the Pro side chain, and owing to the unusual conformation of the activation segment, only the engagement of a Pro residue is favourable because of the absence of a hydrogen-bond acceptor for a substrate main-chain nitrogen. The finding that the Arg side chain at P+3 forms a hydrogen bond to the phosphate of the pThr160 explained the specificity for basic residues at P+3 and revealed another mechanism of phosphoregulation. Later studies on cell cycle kinases would indicate how the peptide–substrate-binding site on CDK2 is linked to the RxL recruitment site on cyclin A (53), and how the CDK2 subunit recognizes cyclin E (60).

These studies provided the basis for a general model for how protein kinases are regulated. However, they also provided structural knowledge of targets for drug discovery in oncology. Louise’s work in 1997 on the relatively non-selective inhibitor staurosporine revealed some of the first details of how ATP competitive inhibitors interacted with CDK2 (47). The staurosporine lactam amide group mimics the hydrogen-bonding interactions of the ATP-adenine ring. Louise developed an active programme in structure-based drug design with therapeutic implications for the cell cycle kinase CDK2 (58) and the transcriptional regulator kinase CDK9 (62).

Diamond light source

Louise was a powerful and enthusiastic advocate of new techniques and instrumentation to advance the scope and capacity of structural biology to address increasingly ambitious questions. In 2003 she accepted the role of Science Director for Life Sciences at the Diamond Light Source in the UK, which was commissioned in January 2007. Her realization in the late 1970s that synchrotron radiation would enable high-resolution structure determination of small and weakly diffracting protein crystals convinced her that synchrotron radiation would play a key role in the future of structural biology. This perfectly complemented the aspiration of Diamond’s first director, Professor Gerhard Materlik (FRS 2011), to appoint a life science director of international repute with strong roots in the community.

From 2003, Louise spent 50% of her time with the University of Oxford and 50% with Diamond, developing beamlines for macromolecular crystallography, non-crystalline diffraction, circular dichroism and infrared microspectroscopy. Together with So Iwata, Liz Carpenter and Gwyndaf Evans, and in collaboration with Imperial College, she established the Membrane Protein Laboratory funded by the Wellcome Trust. Louise also ensured that Diamond had on-site accommodation and facilities for users of the scientific facilities. She championed the X-ray tomography beamlines at Diamond and performed her own experiments with live cells on the X-ray free-electron laser (FLASH) in Hamburg. Louise retired as Director of Life Science in 2008, but retained her association with Diamond as a Diamond fellow.

Education, scholarship, contributions to the scientific community and international science

Louise had a passionate interest in international science and a strong commitment to education, training and scholarship. Her laboratory attracted students and postdocs from around the world, and she established numerous international collaborations to create a vibrant and multi-cultured lab.

Louise spent three years as chair of the Scientific Advisory Committee of the European Molecular Biology Laboratory and several years on the Advisory Board of the Swiss National Centre for Competence in Research. She played a role in the development of science in Islamic countries, lecturing in Iran, Bangladesh and Pakistan, and supported the creation of SESAME, the new synchrotron in Jordan. Her election as an associate fellow of the Third World Academy of Sciences (TWAS) reflected her activity and allowed her to network with a broad range of eminent scientists with similar interests in science in developing countries, and to chair the TWAS selection panel for elections in the fields of cell, structural and molecular biology. Representing the Royal Society, from 1993 to 2001 Louise served as a governor of Westminster School.

In her clear and eloquent writing, Louise would bring the description of protein structure and function to life by endowing them with anthropomorphic qualities. Her lectures were often a sense of occasion, which she would enliven by likening biological processes to characters in works of literature. In one memorable example she drew an analogy to the opening line of Anna Karenina, ‘Happy families are all alike; every unhappy family is unhappy in its own way’ (Tolstoy 1901), to illustrate how all active protein kinases have the same catalytic site structure, whereas there are multiple mechanisms to inactivate protein kinases. This was a wonderful analogy to simplify a complex structural system. It reflected Louise’s clear and accurate thinking and ability to distil and synthesize disparate facts into coherent unifying principles. Louise authored masterly and comprehensive reviews, for example on allostery, protein phosphorylation, Laue protein crystallography and protein kinases (303138394659). Summer vacations were spent teaching at the International Centre for Theoretical Physics in Trieste, founded in 1964 by her husband, Abdus Salam FRS, the Pakistani physicist and Nobel laureate (Physics 1979), and later renamed the Abdus Salam International Centre for Theoretical Physics.

With Tom Blundell (FRS 1984), Louise wrote the classic and influential textbook Protein crystallography (11). Tom recalls: ‘I discovered Louise’s grasp of physics as well as biology when David Phillips asked us to write a review of protein crystallography for Biennial Reviews of Science, Technology and Medicine in July 1971, a task he had failed to start and for which the manuscript was overdue. Louise and I both sacrificed our holidays and Louise completed her sections with brilliant insights into this complex, multidisciplinary research technique. The editor accepted only our concluding section as the review (8) and suggested we write a textbook. This we did, after negotiating a large advance with which Louise bought a horse, as one of her passions was riding.’ The book described crystallographic theory in a clear and accessible manner for non-physicists, and combined this with detailed protocols from the lysozyme and insulin research groups for protein crystallization and structure determination. The book became a ‘classic’. It was an essential resource for the protein crystallographic research community for over 20 years and was still selling on eBay in 2012 for £425.78.

In the early 2000s, Louise joined the authorship team of Wolfgang Baumeister, Alasdair Stevens and Richard Perham on a book entitled Molecular biology of assemblies and machines (65). The project was a monumental undertaking. The book integrated the huge and diverse volume of structural biology information with the relevant biological process and context, providing a detailed and clear description of virtually all cellular processes at the molecular, structural and biochemical level. Sadly, both Louise and Richard Perham died before the book was finalized, but their passion and commitment for the book was shared and continued through to publication by Alasdair and Wolfgang. The success of this achievement is a tribute to the tenacity and meticulous research of the four authors.

Louise’s retirement from the David Phillips professorship in 2007 was commemorated by a symposium organized by Ravi Acharya, David Barford, Jane Endicott and Janos Hajdu. The meeting brought former colleagues, collaborators, students and postdocs together, with speakers and delegates in fields reflecting Louise’s scientific interests, and in which she made her major contributions: structural biology, enzymology, protein phosphorylation and the cell cycle. It was a memorable occasion. Lectures were held in the Oxford University Museum of Natural History, with Eddy Fischer delivering a memorable keynote lecture (figure 8), a concert in the Hollywell Music Room, and a symposium banquet in the dining hall of Christ Church College. The wonderful after-dinner speech by Louise was received with a standing ovation.

Figure 8.
Figure 8. Louise with Eddy Fischer (left) and Ernst Helmreich (right) on the occasion of a symposium marking her retirement from the David Phillips professorship, September 2007. (Photograph courtesy of Janos Hajdu.) (Online version in colour.)

 

Through her wise guidance and support, Louise mentored and influenced the careers of 30 graduate DPhil students and many postdoctoral fellows, and was generous in acknowledging their contributions to work from her laboratory. She was fond of quoting Humphrey Davy (FRS 1803), who, when asked to define his most important discovery, named Michael Faraday (FRS 1924). Louise herself wrote, ‘In many ways I feel that my most important discoveries have been those with whom I have worked and trained’ (61). This captures something of Louise’s unassuming modesty and generosity, which, along with a clear mind and firm conviction, allowed her to influence and inspire those people for the better.

Personal life

In 1962, the year Louise started her PhD research, her interest in science and world affairs took her to the Pugwash Conference in London, where Bertrand Russell FRS spoke, and where she met Abdus Salam, the future Nobel Prize-winning physicist. They were married in 1968. Louise was devoted to their two children, Umar and Sayyeda, who themselves have four children: Martha, Etta, Ilyas and Zakariya. In August 2011 Louise suffered a severe heart attack and was treated at Addenbrooke’s Hospital, Cambridge. She died from this illness on 25 September 2012.

Recognition and awards

Louise’s achievements were recognized by multiple awards and honours, including the Kaj Linderstrom-Lang Prize in 1989 for ‘pioneering contributions to protein crystallography and to our understanding of the structural properties of enzymes, especially through the use of time-resolved X-ray crystallography’, election as Fellow of the Royal Society in 1990, European Molecular Biology Organisation membership in 1991, appointment as an associate fellow of the Third World Academy of Sciences in 2000, the Novartis Medal and Prize of the Biochemical Society in 2009, election as a foreign associate member of the US National Academy of Sciences in 2011, honorary fellowships of the Biochemical Society and British Biophysical Society, and honorary DScs from St Andrews, Bath, Imperial College and Cambridge universities. Louise was awarded Dame Commander in the 2003 Queen’s New Year Honours ‘for services to biophysical sciences’.

In 2020 the British Biophysical Society (BBS) Young Investigator Award, introduced in 2002 to celebrate an outstanding contribution in any area of biophysics made by a young researcher in the UK and Ireland, was renamed the BBS Louise Johnson Early Career Award in recognition of Louise as an outstanding biophysicist and mentor of others, especially in the early stages of their careers.

Honours

1989 Kaj Linderstrom-Lang Prize
1990 Fellow, Royal Society
1991 Member, European Molecular Biology Organisation
1992 Honorary DSc, University of St Andrews
1993 Fellow, University College London
1996 Charmian Medal, Royal Society of Chemistry Award in Enzyme Chemistry
1998 Datta Medal, Federation of European Biochemical Societies
2000 Associate fellow, Third World Academy of Science
2001 Member, Academia Europaea
2001 N. and B. L. Vallee Visiting Professor, Harvard University Medical School
2003 DBE, Queen’s New Year Honours
2004 Honorary DSc, University of Bath
2004 Honorary fellowship, British Biophysical Society
2004 Honorary fellowship, Biochemical Society
2004 Honorary fellowship, Institute of Biology
2005 Foreign fellow, Bangladesh Academy of Sciences
2007 Foreign fellow, American Academy of Arts and Sciences
2008 Visiting professor, University of Karachi
2009 Novartis Medal and Prize, Biochemical Society
2009 Honorary fellow, Royal Society of Chemistry
2009 Honorary DSc, Imperial College London
2010 Honorary ScD, University of Cambridge
2011 Foreign member, US National Academy of Sciences

Acknowledgements

We thank the following for their comments on this memoir: Ravi Acharya, Janos Hajdu, Jennifer Martin, Keith Wilson and Sayyeda Salam. We thank Elspeth Garman for her help researching this memoir.

The frontispiece portrait photograph was taken by A. C. Cooper in 1990 and is © The Royal Society.

Author profiles

David Barford FMedSci FRS

Inline Graphic

David Barford studied for his DPhil with Louise at the Laboratory of Molecular Biophysics, University of Oxford, investigating the allosteric response of glycogen phosphorylase. After postdoctoral research fellowships at the University of Dundee and Cold Spring Harbor Laboratory, New York, he returned to Oxford as a university lecturer and fellow of Somerville College before joining the Institute of Cancer Research in London in 1999 as co-head of the Division of Structural Biology. Since 2013 David has been a group leader at the MRC Laboratory of Molecular Biology, Cambridge.

Thomas Blundell FMedSci FRS

Inline Graphic

Thomas Blundell studied for his DPhil with Herbert Powell FRS at the University of Oxford, and then worked with Dorothy Hodgkin as a member of the team that determined the structure of insulin. Tom’s first research posts were at the Universities of Oxford and Sussex. He joined the Department of Crystallography at Birkbeck, University of London in 1976, becoming head of department in 1978. In 1995 Tom was appointed the Sir William Dunn professor of biochemistry, and head of department, at the University of Cambridge. Tom co-founded Astex Pharmaceuticals. With Louise, Tom co-wrote Protein crystallography, published in 1976.

Footnotes

* Numbers in this form refer to the bibliograpy at the end of the article.

Published by the Royal Society

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Links and Related Essay’s

Louise Johnson – Wikipedia

https://en.wikipedia.org/wiki/Louise_Johnson

Dame Louise Johnson obituary | Biochemistry and molecular biology | The Guardian

University College London – Wikipedia

Dr. Abdus Salam liked white women, alcohol and a busy British lifestyle – ahmadiyyafactcheckblog

Imperial College London – Wikipedia

Amazon.com: Cosmic Anger: Abdus Salam – The First Muslim Nobel Scientist: 9780199697120: Fraser, Gordon: Books

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