Martin Noble

Brief Biography

1985-1988: Undergraduate studies in Natural Sciences at St John’s College, Cambridge University;

1988-1992: 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.

Research 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.

 

Technological 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.