Mark Carr's Research Interests

Structure, Function and Mechanism of Action of Proteins

Publications in International Journals

Current Research Grants

Previous Research Grants

Dr Carr has built up a large and successful research group, which currently contains 5 postdoctoral scientists, 7 Ph.D students, 2 M.Sc students and a research technician, with current research funding of over £2.5 million. His scientific career has concentrated on determining the structures, functions, interactions and mechanisms of action of proteins and protein complexes involved in key biological processes of significant medical importance, which remains the main focus of Dr Carr’s laboratory. A major component of this work has been the successful use of NMR-based methods to determine new protein structures and to investigate protein-drug, protein-protein and protein-DNA interactions. The ongoing research in Dr Carr’s group aims to integrate the information obtained from molecular, cellular and structural biology-based approaches to provide a detailed understanding of the function of proteins involved in disease states, which is an essential prerequisite for a rational, knowledge-based approach to drug discovery and development. In addition, through close collaboration with pharmaceutical companies such as UCB-Celltech his group aim to make a major contribution to the design and development of important new drugs, such as therapeutic antibodies targeted at secreted signalling proteins or cell surface receptors. Current research within the group falls into three main areas, which are outlined below.

Molecular basis of tuberculosis pathogenesis.

Tuberculosis remains one of the most significant bacterial diseases of humans, with about one third of the world’s population infected resulting in over 2 million deaths annually. Research in Dr Carr’s group is focussed on determining the structures, functions and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors, including ESAT-6, CFP-10, Rv0287, Rv0288 and MPB70. We have recently shown that several of the proteins under investigation play key roles in pathogen to host cell signalling and identification of the signalling pathways involved and their affects on host cell behaviour are major focuses of ongoing research. This work is a collaboration with groups at the Central Veterinary Laboratory (Prof. Glyn Hewinson and Dr Mark Chambers), National Institute for Medical Research (Dr Roger Buxton), University of Kent (Dr Richard Williamson), University College, Dublin (Dr Stephen Gordon), Statens Serum Institut, Copenhagen (Dr Ida Rosenkrands) and with several colleagues at Leicester (Dr Bernard Burke and Prof. Mike Barer). Dr Carr’s research group is also an active member of the Mycobacterium Tuberculosis Structural Genomics Consortium, which involves over fifty research laboratories across the world.

Molecular basis of the control of eukaryotic gene expression.

Control of eukaryotic gene expression is dependent upon the assembly of a diverse range of protein-protein and protein-nucleic acid complexes, which are formed in a dynamic and highly regulated process. The main focus of current work in Dr Carr’s group is the highly conserved, eukaryotic protein Pdcd4, which has recently emerged as a key regulator of both transcription and translation, mediated via specific protein-protein and perhaps protein-RNA interactions. Pdcd4 has also been identified as an important new type of tumour suppressor in mammalian cells and has very recently been shown to play an essential role in cellular responses to DNA damage. The overall aim of ongoing work is to determine the molecular basis of the cellular functions of Pdcd4, which should lead to a clearer picture of the functions associated with its role as a tumour suppressor. A major aspect of this work will be the determination of high resolution structures for functional domains of Pdcd4 and tight complexes formed with functional partners, such as eIF4A, eIF4G, c-Jun and p300. This will also be complemented by structure-guided mutagenesis studies aimed at associating interesting surface features of Pdcd4 (potential functional sites) with specific cellular functions, such as its role in DNA damage response. This research programme forms part of a successful and long-term collaboration with Prof. Karl-Heinz Klempnauer’s group at the University of Münster.

Structural characterisation of protein-drug interactions.

High resolution structural information for proteins and protein-ligand complexes now plays a major role in the design, optimisation and patent protection of new therapeutic molecules. In close collaboration with medicinal chemistry, protein biochemistry, molecular biology and therapeutic antibody groups at UCB-Celltech (Dr Richard Taylor, Dr Alistair Henry, Dr Martin Robinson and colleagues) Dr Carr’s group are using NMR spectroscopy-based methods to determine the structures of validated protein drug targets, to map the binding sites for candidate drugs on proteins, and to determine the orientations and conformations of potential drugs bound to target proteins. This approach has proved to be highly successful and informative for both traditional small molecules and for a wide range of potential therapeutic antibodies. Dr Carr’s laboratory are also trying to develop new, improved and more rapid NMR-based approaches to obtain detailed structural information for large protein-drug complexes (50-100 kDa), in particular, for systems that have proved to be intractable to protein crystallography.

fig 1

Solution structure of the functional complex formed by the M.tuberculosis virulence factors ESAT-6 and CFP-10

 

Fig 2

Solution structure of the major secreted M.bovis protein MPB70

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