Atoms and Empty Space: the Structural Biology of Specificity

The eminent structural biologist Laurence Pearl, Professor of Structural Biology in the Genome Damage and Stability Centre at the University of Sussex, has strong links with Birkbeck. He studied for his PhD under Professor (now Sir) Tom Blundell at Birkbeck in what was then the Department of Crystallography (and the only full university department so named in the UK). The latest of the many honours and awards that he has received is the Biochemical Society's prestigious Novartis Medal for 2018. This is an annual award, made "in recognition of contributions to the development of any branch of biochemistry" and the winner is invited to present a lecture either at the Society's London headquarters or at one of its many conferences. Pearl gave his Novartis Medal Lecture, entitled Atoms and Empty Space: the Structural Biology of Specificity at the London office of the Biochemical Society on 13 November 2018.

This lecture was live-streamed on Facebook. It is linked from the Biochemical Society Facebook page, but you don't need to have a Facebook account to view it; just click on the video link below. (It is about an hour long.)

Video © Biochemical Society 2018

To summarise the lecture briefly, Pearl began with a well-known but still controversial quote from the Greek philosopher Democritus: "Nothing exists except atoms and empty space. All else is opinion." He then summarised the beginning of his scientific career as a postgraduate student at Birkbeck. During his PhD he learned computer programming and wrote - or contributed to - some of the first structural bioinformatics programs, as well as studying the structure of the aspartic protease, endothiapepsin (PDB 4APE). This was in the early 1980s, when the world was becoming aware of the scourge of AIDS and the necessity of targeting its viral cause, HIV. Sequencing the tiny HIV genome revealed a protease with similar sequence motifs to aspartic proteases, but less than half as long. It was Pearl, by then a postdoc at the Institute of Cancer Research in London, and Willie Taylor from Birkbeck who predicted, years before the structure was solved, that HIV's protease would be active as a dimer. (There is more about this in section 7 of PPS, on Quaternary Structure.) The HIV protease structure - exactly as Pearl and Taylor had predicted it - became an important tool for the discovery of protease inhibitors as drugs against AIDS. The first protease inhibitor to enter the clinic was named saquinavir after the amino acid motif SQNI that led them to predict the enzyme's dimeric structure.

Not surprisingly, this discovery also proved to be a gateway to Pearl's career as an independent researcher. He set up his lab in 1989 in the biochemistry department at UCL, with research projects in three areas: DNA repair, signal transduction, and a group of unrelated proteins that help other proteins to fold and that have collectively been named chaperones. He spent the rest of his lecture describing just a few of the many proteins that his group has studied during the last 30 years: first at UCL, then back at the Institute of Cancer Research and since 2009 at Sussex. These included the enzyme uracil DNA glycosylase, which is involved in the specific repair of cytosine residues in DNA that have been deaminated to form uracil. His co-worker on this project was Renos Savva, who is now a senior lecturer at Birkbeck and director of our MSc course in Biobusiness. The structure of this enzyme (PDB 1UDI) explains the exquisite specificity of this enzyme. Another, much smaller DNA repair enzyme, mismatch uracil glycosyase, was found to have the same fold. His more recent work, which uses electron microscopy as well as X-ray crystallography, includes the structure and mechanism of glycogen synthase kinase, and the structure and dynamics of further DNA damage and repair systems. Listen to the lecture if you want to find out more!