Tom Blundell's research combines structural biology, structural bioinformatics and structure-guided drug discovery.
Most of his work has been on multi-component protein assemblies - cell surface receptors and intracellular signalling systems - that mediate cell regulation, focusing recently on growth factors such as nerve growth factor (NGF), fibroblast growth factor (FGF) and hepatocyte growth factor/ scatter factor (HGF/SF) and their receptors.
Over the past decade he has extended his work to understanding DNA damage repair signaling, focusing initially on homologous recombination (HR) in the study of Rad51 interactions with BRCA2, and more recently on Non-Homologous End Joining (NHEJ), both of which play major roles in double-strand break DNA repair. In NHEJ a ring-shaped Ku70/Ku80 heterodimer forms first at broken DNA ends, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) binds to mediate synapsis. His group has recently reported a 3D structure of DNA-PKcs in complex with a fragment of Ku. DNA ligase IV (LigIV) is recruited as a complex with XRCC4 for ligation, with XLF/Cernunnos, playing a role in enhancing activity of LigIV. His group has used X-ray crystallography to determine structures of both XRCC4 and XLF. They are now using a combination of methods - X-ray crystallography, electron microscopy, small angle X-ray scattering, nanospray mass spectrometry, ITC and SPR - to gain insights the organisation of higher order complexes.
Tom Blundell has developed widely used software in structural bioinformatics, including databases databases of three-dimensional structures of proteins (CREDO, PICCOLO, BIPA), software for sequence-structure (fold) recognition (FUGUE) and software for comparative modeling (COMPOSER, MODELLER, ORCHESTRAR, RAPPER). The current focus is on the identification and analysis of drug targets, especially those in Mycobacterium tuberculosis and Man, and on the analysis of the roles of nsSNPs and somatic mutations in human disease.
These interests have led to extensive work on structure-guided drug discovery. In the 1970s and 80s Tom Blundell focused on structure-guided approaches to lead optimization, particularly antihypertensives targeted to renin, and AIDS antivirals, against HIV proteinase. In the past two decades he has become interested in fragment-based approaches to lead discovery, co-founding Astex Therapeutics http://www.astex-therapeutics.com/ and has established collaborative academic groups in the University funded by the Bill and Melinda Gates Foundation, by the Wellcome Trust and by European Union, against both difficult targets (multiprotein systems) and neglected diseases (tuberculosis).
Noha Abdel-Rahman, Michal Blaszczyk, Victor Bolanos-Garcia, Dimitri Chirgadze, Marcio Dias, Sungsam Gong, Alicia Higueruelo, Anjum Karmali, Semin Lee, Ann Ling, Bernado Ochoa Montano, Takashi Ochi, Will Pitt, Adrian Schreyer, Lynn Sibanda, Anna Sigurdardottir, Leonardo Silvestre, Jawon Song, Sachin Surade, Qian Wu.
Our research is focused on understanding protein-protein interactions in various cellular systems. One of the main targets of our research has been the members of the TGFbeta family of growth factors, in particular Activins. These proteins play a vital role in the early embryonic development in vertebrates and are responsible for the development of mesodermal structures in the embryo. They are also foudn to be essential for maintenance of pluripotency in cultured human embryonic stem cells. Activins signal through two different receptors, called the type I and type II, and their activities are regulated by inhibitory proteins that can inactivate these growth factors by binding them and preventing interactions with receptors. Follistatin is a high affinity inhibitor of activins, and we have recently solved the crystal structure of the minimal activin interacting fragment of follistatin in complex with activin. We are also interested in heparan sulphate binding to follistatin and how it regulates follistatin function, and are currently in progress of studying these interaction in more detail.
We are also studying the structure and function of modular growth factors of the CCN family. These are extracellular proteins involved in cell-cell signalling, wound healing and angiogenesis, among other things. Our aim is to elucidate the three dimensional structures of the individual domains and study the function of the isolated, purified domains in various cellular processes in collaboration with cell biologists.
We have recently moved to the area of fragment based drug discovery and are developing methods to inhibit various kinds of protein-protein interactions with an aim to design both chemical tools for cellular studies and, potentially, lead compounds for drug development. This is highly interdisciplinary project in which biologists, crystallographers, biophysists, chemists and computational chemists work in close collaboration.
Cat Donaldson, Sandra Grieve, Ye Gu, May Marsh, Katharina Ravn, Tim Sharpe, Eugene Valkov, Emma Xu
Our aim is to understand how fundamental cellular processes are controlled through molecular interactions in multi-component assemblies.
The expression of genetic information can be regulated by controlling the life time of mRNA to fine tune an organism's response to developmental or environmental stimuli. In the bacterium, Escherichia coli, this is regulated by an multi-enzyme assembly called the RNA degradosome. We are exploring the structure and function of the RNA degradosome assembly. The structure of the catalytic domain in complex with RNA substrate is shown in the figure below.
We are studying thiamine-dependent, multi-enzyme assemblies from central metabolism. We have also undertaken a collaborative study of bacterial systems which transport proteins and antibiotics outside of the cell. A structural view of this system will help us to understand the molecular bases of virulence and drug resistance in the Gram-negative family of bacteria.
We directly visualise the individual components and their complexes at an atomic level using X-ray diffraction to reveal the intricate and subtle structures which underlie these complexes. We also use a number of other techniques such as non-dissociating mass spectrometry, neutron and X-ray solution scattering, and calorimetry to analyse macromolecular complexes.