1985-1988: Undergraduate studies in Natural Sciences at St John’s College, Cambridge University;
Ph. D. in X-ray crystallography and drug design at the European
Molecular Biology Laboratory, Heidelberg and the Rijksuniversiteit,
Groningen; 1993-1995: Postdoctoral studies with Professor Dame Louise
Johnson, Laboratory of Molecular Biophysics, Oxford University;
1995-1999: Royal Society University Research Fellow, Laboratory of
Molecular Biophysics, Oxford University; 1999-2004: University Lecturer
in Structural Biology, Laboratory of Molecular Biophysics, Oxford
University; 2004-2011: Professor of Structural Biology, Laboratory of
Molecular Biophysics, Oxford University; 2008-2011: Head of Laboratory,
Laboratory of Molecular Biophysics, Oxford University; 2011-Present:
Professor of Structural Biology and Anticancer Drug Discovery, Northern
Institute for Cancer Research, Newcastle University.
throughout my career has focussed on understanding the relationship
between structure and function in proteins that are of biomedical
importance, especially where they play a role in determining cellular
fate. The family of proteins where I have made most contributions is the
cyclin-dependent protein kinases, enzymes that control transcription
and cell division: unsurprisingly, the regulation and dysregulation of
this family is closely connected to cancer. Work on CDKs forms the bulk
of my publications, and includes widely cited scholarly reviews in Cell,
Science, and ARB
Interest in biomedically relevant proteins has
driven my work with proteins that are implicated in the molecular
pathology of sleeping sickness (T. brucei triosephosphate isomerase),
malaria (P. falciparum PK5), tuberculosis (M. smegmatis NAT), and cancer
(CDKs, MDM2 and CD44). For several of these targets I have helped
develop potent and selective inhibitors, some of which are patented and
may be clinically developed.
My interest in
structure-function relationships has lead me into computer programming,
in which area I have been chairman of CCP4, and coded for packages that
include Coot and CCP4MG.
Finally, I have also developed an
interest in exploiting macromolecular architecture for nanotechnological
purposes, being co-inventor of crysalins, a new class of material based
on highly symmetric protein assemblies, the invention of which was
published in Nature Nanotechnology, and on the basis of which a spin-out
company currently employs seven people in Oxfordshire, UK.
Preparing for the flood: the data storm facing structural biologists in drug discovery and electron microscopy
For fifty years, structural biology has played a central role in
dissecting the molecular mechanisms that underpin life. Overwhelmingly,
this contribution has arisen from successes in resolving atomic
structures of biological macromolecules by X-ray crystallography.
Electron microscopy has, to date, complemented this work by enabling the
imaging of larger scale structures at lower resolution. Now, advances
in sources, detectors and software stand to revolutionise the roles of
these two techniques.
For macromolecular X-ray crystallography,
the throughput enabled by technological advances is allowing it to
become a first-line technique that is useful for identifying small
molecular “fragment” hits which chemists can develop into drugs. For
this purpose, hundreds of crystals are treated with cocktails of
fragments, and diffraction data are collected from each. The analysis
and interrogation of the resulting datasets presents interesting challenges which will be discussed in my talk.
advances have also transformed the relevance of electron microscopy for
structural biology. Cryoelectron microscopy can now define the
structures of even relatively small macromolecules (molecular weight
~100kilodaltons), at essentially atomic resolutions. Deriving these high
resolution structures requires the analysis of hundreds of electron
micrographs to capture and exploit hundreds of thousands of views of the
macromolecule being studied.
I will describe how we are applying a
nanotechnological approach to protein engineering, in order to advance
structural biology through both X-ray crystallography and electron
microscopy, especially so as to enable drug discovery.