Professor Nicholas Keep (known to generations of Birkbeck students as Nick) was appointed to a chair in biomolecular structure in 2009. It was June 2011, however, before he gave his inaugural lecture at the college. In this lecture he gave an overview of the techniques he uses as an experimental structural biologist and some of the discoveries he has made through them.
Nick’s career so far has been a glittering one. He took both his degrees at Cambridge and did postdoctoral work at UCL and back in Cambridge at the prestigious Laboratory of Molecular Biology (LMB) before being appointed as a lecturer at Birkbeck in the mid-90s. Since then he has risen steadily through the ranks and is now not only Professor but Executive Dean, with academic and financial oversight of the whole Faculty of Science. It is perhaps not surprising that it took him two years to fit in his inaugural lecture.
He began his lecture with a whistle-stop tour of the history of structural biology, beginning at Birkbeck and with the first Professor of Crystallography here, J.D. Bernal (see June 2008 post). Before he even arrived in London, however, Bernal had published (with Dorothy Hodgkin) the first ever diffraction pattern to be obtained from a protein crystal. Very much later, Nick as an undergraduate Cambridge student was inspired by two Nobel laureates, Max Perutz (who published the first-ever three-dimensional protein structure, that of myoglobin, in 1958) and Tim Hunt, to specialise in this aspect of molecular science. His PhD research was on the structure of methylmalonyl-coA mutase , an enzyme that binds to vitamin B12. This provides another link back to Dorothy Hodgkin, whose Nobel Prize in 1964 was awarded partly for determining the structure of this important vitamin.
He then spent a few minutes going through the essential principles of protein crystallography. This involves purifying and crystallising a protein and then exposing the crystals to a parallel beam of X-rays. These X-rays are deflected from the atoms in the crystal in a regular way to produce a diffraction pattern, and this can be interpreted to give first a map showing the density of electrons in the molecule, and then a model of the positions in space of all atoms in the molecule (missing out, in most cases, the lightest atom, hydrogen). In an ideal case, this whole process can now take a month or so, but this is rare: many structures still take years to solve. Birkbeck now has excellent facilities for purifying proteins and growing crystals. We can collect the X-ray data on site but often go to more powerful machines – synchrotrons – located in the UK and beyond. Britain’s first synchrotron is still in use, but in Jordan; it was replaced about five years ago by a state-of-the-art facility, Diamond , near Harwell in Oxfordshire. Birkbeck’s scientists also use synchrotrons elsewhere in Europe; Nick’s favourite is in Grenoble.
Nick then went on to describe some of the research projects that he has led or contributed to at Birkbeck. Working with Lin Field and Jing-Jiang Zhou at Rothamsted Research in Hertfordshire, he solved the structure of an insect protein that binds odorant molecules, which has led to some useful insights into the mechanism behind insects’ extremely sensitive sense of smell. Much of his work, however, is and has been in proteins that are involved in one way or another with human disease. Duchenne Muscular Dystrophy is a progressive, muscle-wasting genetic disorder that almost always affects boys and that is caused by mutations in a large muscle protein called dystrophin. Nick and his colleagues have solved the structures of a part of this protein that binds to another muscle protein, actin, and of related proteins.
It was only when he reached some of his final examples that the pun in his title, “Waking up to Structural Biology”, became clear. The bacterium Mycobacterium tuberculosis (see also April 2011 post ) infects the lungs of about a third of the world’s population. In most people, however, it remains in a wholly benign, dormant condition. In about 5-10% of cases, however, the dormant bacteria will “wake up” when an infected individual is under stress (for example, by exposure to another infection) and overt tuberculosis (TB) develops. Bacteria in the dormant stage are untreatable by any current TB drugs. Nick and his group first studied the structure and function of a protein known as resuscitation promoting factor that is involved in this “waking up” process,. He observed similarities between its sequence and that of a very well-known protein, lysozyme , which breaks down bacterial cell walls, and later, when the structure was solved, it was seen to have a lysozyme-like fold. This led to his identification of a glutamate residue as key to this enzyme’s activity. He is now looking at other proteins involved in M. tuberculosis resuscitation including a small heat shock protein (a protein that helps keep other protein structures stable under stresses such as raised temperatures), Acr1. This is the most abundant protein in dormant TB. He ended with a glimpse of a new unpublished TB protein structure.
Nick concluded a fascinating lecture by thanking his lengthy list of co-authors and particularly his research group, stressing the collaborative nature of science, and Gabriel Waksman, head of the Department of Biological Sciences, closed the proceedings by praising his achievements in teaching and administration as well as research.
Both second-year options in the MSc Structural Molecular Biology programme are concerned with the techniques used to study the structures of biomolecules. Techniques in Structural Molecular Biology (TSMB) is a general course covering crystallography, NMR, electron microscopy and some of the molecular biology and bioinformatics techniques associated with them, whereas Protein Crystallography (PX) is, as its name implies, a more specialist course.