Introduction

Research Groups

Select Research Group Head Prof. Sir Tom Blundell Prof. Kevin Brindle Dr Bill Broadhurst Dr Guy Brown Dr Mark Carrington Prof. Paul Dupree Prof. Gerard Evan - Head of Dept Prof. Richard Farndale Dr Giorgio Favrin Dr Jenny Gallop Dr Nick Gay Dr Andrew Grace Dr Jules Griffin Dr Brian Hendrich Dr Andrew Hesketh Dr Robin Hesketh Dr Matt Higgins Dr Florian Hollfelder Dr Hee-Jeon Hong Prof. Chris Howe Dr Marko Hyvonen Prof. Steve Jackson Dr Tony Jackson Prof. Richard Jackson Prof. Ernest Laue Prof. Peter Leadlay Dr Kathryn Lilley Dr Karen Lipkow Dr Rick Livesey Prof. Ben Luisi Dr Sarah Lummis Dr Juan Mata Dr John McCafferty Prof. Jim Metcalfe Dr Masanori Mishima Dr Eric Miska Dr Tom Monie Dr Helen Mott Dr Natasha Murzina Dr Daniel Nietlispach Dr Darerca Owen Prof. Steve Oliver Dr Luca Pellegrini Dr Markus Ralser Dr Nick Robinson Prof. George Salmond Dr Deirdre Scadden Dr José Silva Prof. Austin Smith Prof. Chris Smith Dr Nancy Standart Prof. Dame Jean Thomas Dr Aviva Tolkovsky Dr Martin Welch Dr Joyce Wong Dr Nianshu Zhang

Service & Research Support Facilities

Select by Subject or Manager DNA Sequencing Facility . . . . . Mr John Lester _______________________________ Quantitative Proteomics . . . . . Dr Kathryn Lilley _______________________________ Proteomics Core Services . . . . . Dr Mike Deery _______________________________ Protein & Nucleic Acid Chemistry . . . . . Dr Len Packman _______________________________ Metabolomics . . . . . Dr Jules Griffin _______________________________ Baculovirus Facility . . . . . Dr Darerca Owen _______________________________ Biophysics Facility . . . . . Dr Katherine Stott _______________________________ Crystallographic X-ray Facility . . . . . Dr Dima Chirgadze _______________________________ NMR spectroscopy . . . . . Dr Daniel Nietlispach _______________________________ Fermentation Facility . . . . . Dr Nianshu Zhang _______________________________ Bioinformatics & Computational Biology Services . . . . . Dr Jenny Barna _______________________________ Computer & IT Support . . . . . Dr Erik Timmers _______________________________

Past members last known active weblink

Select past member of Department Dr Stephen Bell Prof. Jonathan Blackburn Dr David Brown Dr Pak-Lee Chau Dr Hal Dixon (deceased) Dr Jessica Downs Prof. David Ellar Dr Paul Kemp Dr Simon Lovell Dr Kenji Mizuguchi Dr Massimo Paoli Prof. Richard Perham Dr Peter Reynolds Dr Philip Rubery Dr Gerry Smith Dr Margaret Sunde Prof. Jamie Vandenberg Dr Kira Weissman

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Specificity, regulation and inhibition of protein-protein interactions in cell signalling

Research Groupings: Structural and molecular cell biology | Developmental and regenerative biology and medicine

We are interested in understanding how various signalling proteins interact with other signalling proteins as well as other ligands such as heparan sulphates and lipids. We are trying to understand how these interactions are regulated and how we could manipulate these interactions in vivo and in vitro. We use bioochemical and biophysical techniques to study these molecules, and whenever possible, try solve their three dimensional structures using X-ray crystallography.

Crystal structure of human activin A (red and orange) in complex with two domain fragment of follistatin (blue-green)   See larger image

One of the system we have studied in detail is the extracellular regulation of TGFβ family growth factors. This is a large family of related proteins with over thirty members in humans. There are only a few receptors which transmit the signals from this large number of ligands and one of the things we are interested in are the determinants of signalling specificity. Many TGFβ proteins interact also with various regulatory proteins which can modulate their function, typically by preventing interactions with the receptors. We have studied the interactions activin with its high affinity inhibitor follistatin and the interactions of follistatin with heparan sulphate. Several TGFβ family proteins are key developmental regulators, and many of our project are in collaboration with developmental and stem cell biologists.

We are also in progress of determining structures of CCN family growth factors. This class of proteins is characterised by its modular structure made of an IGF-binding domain, a von Willebrandt type C domain, a thrombospondin type 1 repeat and a C-terminal cystine-knot domain. Our efforts are focused on determining three dimensional structures of these modules either in isolation, or if possible, in the context of the full-length protein. We are also studying their biological function with our collaborators.

We are members of the Cambridge Molecular Therapeutics Programme, an interdisplinary research consortium applying novel methods to the development of inhibitors against clinically relevant targets in cancer and infectious diseases, both for potential use as drugs and as chemical tools. We are in charge of the structural biology aspect of various fragment-based inhibitor development programmes between the groups Prof. Tom Blundell, Prof. Chris Abell, Prof. Ashok Venkitaraman and Dr David Spring.

Structure of RAD51 in complex with BRC4 repeat of BRCA2 with the key interaction pockets in RAD51 highlighted in red (PDB:1n0w, Pellegrini et al, 2002)

One of the ways we try to interrupt biological processes is by inhibiting specific protein-protein interactions. There are traditionally seen as very difficult targets for chemical intervention as the interacting surfaces often lack the deeper pockets and clefts found in enzyme active sites. Yet increasing number of examples in the literature shows that at least some interactions can be inhibited by small molecules, and one or two have even made it to the clinical trials. Although none are yet on the market as drugs, there is a growing interest both in academia and in the pharmaceutical industry to target protein-protein interactions. We hope not only to develop new lead compounds for drug development but also to create chemical tools that can be used in fundamental research to study the target protein's function.

One of the targets in this programme is RAD51, a human recombinase required for DNA repair by homologous recombination. Our aim is to develop specific inhibitors against the interaction between RAD51 and BRCA2 for eventual use as novel anti-cancer agents. We use fragment-based methods to develop these inhibitors, and employ calorimetry, X-ray crystallography and protein engineering amongst other techniques to guide the development process.

Lab members
Cat Donaldson, Sandra Greive, Ye Gu, May Marsh, Katharina Ravn, Tim Sharpe, Adrian Schreyer, Eugene Valkov, Emma Xu

References