Structural & functional studies of protein molecules involved in cancer and infectious or metabolic diseases

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Our principle interest is to understand the basic science underlying the mode of action of protein molecules important in disease states. Current activities fall into three main areas. Two of these, the regulation of chromatin structure and transcription, and the mechanisms involved in signal transduction pathways, impact on our understanding of the causes of cancer. Our third area of interest concerns understanding the mode of action of proteins that are directly implicated in infectious or metabolic diseases. Our principle aim is to use protein crystallography, biochemical and biophysical techniques, together with cell biological approaches carried out with suitable collaborators, to gain insights into how these systems function at the molecular level. An additional objective of all our work is to be vigilant for any findings that may enable the development of therapeutic approaches towards any of these disease states. In such cases, we seek to use our understanding of the relevant systems to facilitate the translation of our ideas or reagents to suitable partners for development and exploitation.

Technical Summary

The aim of our research is to use structural biology to probe the mechanisms of protein molecules fundamental to cellular and disease processes. Our main approach involves structure determination by x-ray crystallography integrated with biochemical, biophysical and cell-biological experiments to facilitate and interpret our structural data. We work on protein/protein or protein/ligand interactions that either involve fundamental cellular regulatory systems like signalling via small GTPases or chromatin regulation by methylation or proteins important in major disease areas such as the surface glycoproteins of influenza virus or the major kinases complexes implicated in the development of type II diabetes. Wherever appropriate we seek to exploit our findings for pharmacological benefit through patenting and partnership with MRCT. We are working on the structural basis of signalling of the small GTPase Arf through its interaction and regulation of BAR domain protein arfaptin. We use x-ray crystallography as well as negative stain and cryo electron microscopy to understand the molecular basis of membrane remodelling by this system. In collaboration with our Division of Molecular Neuroendocrinology we are determining the physiological role of this system in controlling vesicle transport across the Golgi. Our interest in chromatin regulation through post-translational modifications has led us into working on polycomb repressive complex (PRC) which is a histone methyltransferase strongly implicated in the development of prostate cancer. We are using protein chemistry, molecular biology and x-ray crystallography to address the molecular mechanism of this large protein complex. Our principle collaborator is with Prof Danny Reinberg. As part of our longstanding collaboration with the Division of Virology we are working on the structural and functional characterisation of the two principle surface glycoproteins of influenza; neuraminidase (NA) and hemagglutinin (HA). With NA we are working with MRCT to develop novel inhibitors of this enzyme to expand the current range of anti-virals effective against influenza (Tamiflu & Relenza). We are using x-ray crystallography to understand the basis of drug binding/specificity and the basis of resistance mutations. On HA we are using x-ray crystallography and biochemical and biophysical approaches to understand the basis of the specificity of host cell interactions. This work is closely informed by the work of the World Influenza Centre housed at Mill Hill and is an important contribution to the surveillance effort. In collaboration with Prof Dave Carling we are investigating the mechanisms of the diabetes-associated kinases AMPK and LKB1. We are using protein chemistry, molecular biology and x-ray crystallography to determine the structure/function relationship in these enzymes with the ultimate aim of informing the development of novel drugs for targeting diabetes.

Publications

10 25 50
 
Description Influence of drug resistant influenza on public health policy
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in advisory committee
 
Description GlaxoSmithKline
Amount £55,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 01/2009 
End 01/2011
 
Description MRC Influenza Grant (2006)
Amount £293,600 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2006 
End 01/2010
 
Description Wellcome-Research Grant-2009
Amount £163,760 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2012
 
Title AMP kinase crystal structure 
Description Protein 
Type Of Material Biological samples 
Provided To Others? No  
Impact Material transferred to company July 2009 
 
Description Epigenetic targets for cancer therapy 
Organisation Constellation Pharmaceuticals
Country United States 
Sector Private 
PI Contribution We have supplied expertise, materials and licence to patent.
Collaborator Contribution Insights into protein behaviour
Impact Helped inform direction of Constellation's research strategy
Start Year 2009
 
Description Studies on AMPK with AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have supplied expertise, materials and advice to GSK, as well as a licence to a patent for their type 2 diabetes drug program.
Collaborator Contribution Insight into protein behaviour
Impact Facilitated by the development of AstraZeneca program
Start Year 2012
 
Description Studies on AMPK with GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We have supplied expertise, materials and advice to GSK, as well as a licence to a patent for their type 2 diabetes drug program.
Collaborator Contribution Insights into protein behaviour
Impact Facilitated the development of GSK program
Start Year 2008
 
Title AMP Kinase Crystal Structure 
Description Insights into nucleotide regulation of cellular energy balance from functional and structural studies. 
IP Reference  
Protection Protection not required
Year Protection Granted 2007
Licensed Yes
Impact UK patent applied for Aug 2007, access to patented information supplied on licence to GSK
 
Title Crystal structure of EED 
Description Crystal structure of EED bound to an analogue of tri-methyl lysine. 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Yes
Impact Patent applied for Dec 2008. Licensed to company.
 
Title N1 Crystal Structure 
Description Structure of Group-1 influenza neuraminidases reveals unexpected difference close to the active site that has potential for novel drug development. 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Yes
Impact IP licensed to University of St Andrews, Nov 2007. Patent granted in China.
 
Description School Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact The students visited the NIMR to hear short research talks and participate in a number of workshops including practical crystallography, chemistry and using microscopes to view chick embryos, flies etc.

Generated interest in the molecular aspects of biological science research.
Year(s) Of Engagement Activity 2012,2013
URL http://www.nimr.mrc.ac.uk/schools/schools-day/