Mark Carr

Tel: +44 (0)116 229 7075 Mark Carr
Email: mdc12@le.ac.uk

Personal details

  • D.Phil University of Oxford 1987
  • Royal Society Postdoctoral Fellow (European Science Exchange programme) and Max-Planck-Society Postdoctoral Fellow, Abteilung Biophysik, Max-Planck-Institut fur Medizinische Forschung, Heidelberg, Germany 1987-89
  • MRC Postdoctoral Fellow, National Institute for Medical Research, London 1989-93
  • Group Leader, Laboratory of Molecular Structure, National Institute for Biological Standards and Control, London 1993-96
  • Lecturer in Structural Biology, Department of Biosciences, University of Kent 1997-2001
  • Reader in Biochemistry, NMR Centre 2001
  • Professor of Biochemistry, 2009

Publications

Please note that the corresponding authors for papers are denoted by *

  1. Lightbody KL, Ilghari D, Waters LC, Carey G, Bailey MA, Williamson RA, Renshaw PS, Carr MD.* (2008) Molecular features governing the stability and specificity of functional complex formation by Mycobacterium tuberculosis CFP-10/ESAT-6 family proteins. J. Biol. Chem. in press, advance online publication 21 April 2008, doi/10.1074/jbc.M800123200.
  2. Veverka V, Crabbe T, Bird I, Lennie G, Muskett FW, Taylor RJ, Carr MD.* (2008) Structural characterization of the interaction of mTOR with phosphatidic acid and a novel class of inhibitor: compelling evidence for a central role of the FRB domain in small molecule-mediated regulation of mTOR. Oncogene 27, 585-595.
  3. Waters LC, Veverka V, Böhm M, Schmedt T, Choong PT, Muskett FW, Klempnauer K-H, Carr MD.* (2007) Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterisation of its interaction with eIF4A. Oncogene 26, 4941-4950.
  4. Waters LC, Yue B, Veverka V, Renshaw P, Bramham J, Matsuda S, Frenkiel T, Kelly G, Muskett FW, Carr MD.*, Heery DM. (2006) Structural diversity in p160/CREB-binding protein coactivator complexes J.Biol. Chem 281, 14787-14795
  5. Waters LC, Böhm M, Veverka V, Muskett FW, Frenkiel TA, Kelly GP, Prescott A, Dosanjh NS, Klempnauer K-H, Carr MD.* (2006) NMR assignment and secondary structure determination of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4. J. Biomol. NMR 36, S5, 18.
  6. Veverka V, Gregor L, Crabbe T, Bird I, Taylor RJ, Carr MD.* (2006) Letter to the Editor: NMR assignment of the mTOR domain responsible for rapamycin binding. J. Biomol. NMR 36, S5, 3.
  7. Renshaw PS, Lightbody KL, Veverka V, Muskett FW, Kelly G, Frenkiel TA, Gordon SV, Hewinson RG, Burke B, Norman J, Williamson RA, Carr MD.* (2005) Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6. EMBO J. 24, 2491-2498.
  8. Marei A, Ghaemmaghami A, Renshaw P, Wiselka M, Barer M, Carr MD, Ziegler-Heitbrock L.* (2005) Superior T cell activation by ESAT-6 as compared with the ESAT-6·CFP-10 complex. Int. Immunol. 17, 1439-1446.
  9. Lightbody KL, Renshaw PS, Collins ML, Wright RL, Hunt DM, Gordon SV, Hewinson RG, Buxton RS, Williamson RA, Carr MD.* (2004) Characterisation of complex formation between members of the Mycobacterium tuberculosis complex CFP-10/ESAT-6 protein family; towards an understanding of the rules governing complex formation and thereby functional flexibility. FEMS Microbiol. Lett. 238, 255-262.
  10. Renshaw PS, Veverka V, Kelly G, Frenkiel TA, Williamson RA, Gordon SV, Hewinson RG, Carr MD.* (2004) Letter to the Editor: Sequence-specific assignment and secondary structure determination of the 195-residue complex formed by the Mycobacterium tuberculosis proteins CFP-10 and ESAT-6: Towards an understanding of their role in tuberculosis pathogenesis. J. Biomol. NMR 30, 225-226.
  11. Carr MD*, Bloemink MJ, Dentten E, Whelan AO, Gordon SV, Kelly G, Frenkiel TA, Hewinson RG, Williamson RA. (2003) Solution structure of the Mycobacterium tuberculosis complex protein MPB70: from tuberculosis pathogenesis to inherited human corneal disease. J. Biol. Chem. 278, 43736-43743.
  12. Jones G, Howard M, McIntosh P, Williamson RA, Carr MD.* (2003) Letter to the Editor: Sequence-specific assignment of the B-Myb DNA-binding domain (B-MybR2R3) bound to a 16 base-pair DNA target site corresponding to a regulatory site from the tom-1 gene.  J. Biomol. NMR 26, 375-376.
  13. Renshaw PS, Panagiotidou P, Whelan A, Gordon SV, Hewinson RG, Williamson RA, Carr MD.* (2002) Conclusive evidence that the major T-cell antigens of the M. tuberculosis complex  ESAT-6 and CFP-10 form a tight, 1:1 complex and characterisation of the structural properties of ESAT-6, CFP-10 and the ESAT-6-CFP-10 complex: implications for pathogenesis and virulence. J. Biol. Chem. 277, 21598-21603.
  14. Williamson RA*, Hutton M, Vogt G, Rapti M, Knauper V, Carr MD, Murphy G. (2001) Tyrosine 36 plays a critical role in the interaction of the AB loop of TIMP-2 with matrix metalloproteinase-14. J. Biol. Chem. 276, 32966-32970.
  15. Lemercinier X, Muskett FW, Cheeseman B, McIntosh PB, Thim L, Carr MD.* (2001) High resolution solution structure of human intestinal trefoil factor and functional insights from detailed structural comparisons with the other members of the trefoil family of cell motility factors. Biochemistry 40, 9552-9559.
  16. Bloemink MJ, Kemmink J, Dentten E, Muskett FW, Whelan A, Sheikh A, Hewinson G, Williamson RA*Carr MD.*(2001) Sequence-specific assignment and determination of the secondary structure of the 163 residue M. tuberculosis and M. bovis antigenic protein mpb70. J. Biomol. NMR 20, 185-186.
  17. Williamson RA*, Muskett FW, Howard MJ, Freedman RB, Carr MD.* (1999) The effect of matrix metalloproteinase complex formation on the conformational mobility of tissue inhibitor of metalloproteinases-2 (TIMP-2). J. Biol. Chem. 274, 37226-37232.
  18. Muskett FW, Frenkiel TA, Feeney J, Freedman RB, Carr MD*, Williamson RA.* (1998) High resolution structure of the N-terminal domain of tissue inhibitor of metalloproteinases-2 and characterisation of its interaction site with matrix metalloproteinase-3. J. Biol. Chem. 273, 21736-21743.
  19. McIntosh PB, Frenkiel TA, Wollborn U, McCormick JE, Klempnauer K-H, Feeney J, Carr MD.* (1998). Solution structure of the B-Myb DNA-binding domain: a possible role for conformational instability of the protein in DNA-binding and control of gene expression. Biochemistry 37, 9619-9629.
  20. Bloch C, Patel SU, Baud F, Zvelebil M, Carr MD, Sadler P, Thornton, JM.* (1998) 1H NMR structure of an antifungal g-thionin protein SIa1: similarity to scorpion toxins. Proteins: Struct. Funct. Genet. 32, 334-349.
  21. Williamson RA*Carr MD*, Frenkiel TA, Feeney J, Freedman RB. (1997) Mapping the binding site for matrix metalloproteinase on the N-terminal domain of the tissue inhibitor of metalloproteinase-2 by NMR chemical shift perturbation. Biochemistry 36, 13882-13889.
  22. Carr MD*, Wollborn U, McIntosh PB, Frenkiel TA, McCormick JE, Bauer CJ, Klempnauer K-H, Feeney J. (1996) Structure of the B-Myb DNA-binding domain in solution and evidence for multiple conformations in the region of repeat-2 involved in DNA-binding: implications for sequence-specific DNA-binding by Myb proteins. Eur. J. Biochem. 235, 721-735.
  23. Williamson RA*, Natalia D, Gee CK, Murphy G, Carr MD, Freedman RB. (1996) Chemically and conformationally authentic active domain of human tissue inhibitor of metalloproteinases-2 refolded from bacterial inclusion bodies. Eur. J. Biochem. 241, 476-483.
  24. Polshakov VI, Frenkiel TA, Westley B, Chadwick M, May F, Carr MD, Feeney J.* (1995) NMR-based structural studies of the pNR-2/pS2 single domain trefoil peptide. Similarities to porcine spasmolytic peptide (pSP) and evidence for a monomeric structure. Eur. J. Biochem. 233, 847-855.
  25. Williamson RA, Martorell G, Carr MD*, Murphy G, Docherty AJP, Freedman RB, Feeney J. (1994). Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family. Biochemistry 33, 11745-11759.
  26. Carr MD*, Bauer CJ, Gradwell MJ, Feeney J. (1994). Solution structure of a trefoil-motif-containing  cell growth factor, porcine spasmolytic protein. Proc. Natl. Acad. Sci. U.S.A. 91, 2206-2210.
  27. De A, Brown DG, Gorman MA, Carr MD, Sanderson MR, Freemont P.S.* (1994). Crystal structure of a disulfide-linked trefoil motif found in a large family of putative growth factors. Proc. Natl. Acad. Sci. U.S.A. 91, 1084-1088.
  28. Soteriou A, Carr MD, Frenkiel TA, McCormick JE, Bauer CJ, Sali D, Birdsall B, Feeney J.* (1993). 3D 13C/1H NMR-based assignments for side-chain resonances of Lactobacillus casei dihydrofolate reductase. Evidence for similarities between the solution and crystal structures of the enzyme. J. Biomol. NMR 3, 535-546.
  29. Ostler G, Soteriou A, Moody CM, Khan JA, Birdsall B, Carr MD, Young D, Feeney J.* (1993). Stereospecific assignments of the leucine methyl resonances in the 1H nuclear magnetic resonance spectrum of L.casei dihydrofolate reductase. FEBS Lett. 318, 177-180.
  30. Soteriou A, Carr MD, Frenkiel TA, Bauer CJ, McCormick JE, Birdsall B, Feeney J.* (1993). Essentially complete 13C, 15N and 1H resonance assignments for the methotrexate complex of Lactobacillus casei dihydrofolate reductase, based on isotopic labelling of the protein with 2H, 13C and 15N and multidimensional NMR spectroscopy. J. Cell. Biochem. 17, 285.
  31. Carr MD.* (1992). 1H NMR-based determination of the secondary structure of porcine pancreatic spasmolytic polypeptide: one of a new family of trefoil motif containing cell growth factors. Biochemistry 31, 1998-2004.
  32. Carr MD*, Mott RF. (1991). The transcriptional control proteins c-Myb and v-Myb contain a basic region DNA binding motif. FEBS Lett. 282, 293-294.
  33. Carr MD, Birdsall B, Frenkiel TA, Bauer CJ, Jimenez-Barbero J, Polshakov VI, McCormick JE, Roberts GCK, Feeney J.* (1991). Dihydrofolate reductase: sequential resonance assignments using 2D and 3D NMR and secondary structure determination in solution. Biochemistry 30, 6330-6341.
  34. Feeney J*, Bauer CJ, Frenkiel TA, Birdsall B, Carr MD, Roberts GCK, Arnold JRP. (1991). Deceptively simple exchange effects in homonuclear Hartmann-Hahn (HOHAHA) spectra of protein-ligand complexes. J. Magn. Reson. 91, 607-613.
  35. Frenkiel TA*, Bauer CJ, Carr MD, Birdsall B, Feeney J. (1990). HMQC-NOESY-HMQC, a three dimensional NMR experiment which allows detection of nuclear Overhauser effects between protons with overlapping signals. J. Magn. Reson. 90, 420-425.
  36. Feeney J*, Birdsall B, Ostler G, Carr MD, Kairi M. (1990). A novel method of preparing totally a-deuterated amino acids for selective incorporation into proteins: application to the assignment of 1H resonances of valine residues in dihydrofolate reductase. FEBS Lett. 272, 197-199.
  37. Birdsall B, Tendler SJB, Arnold JRP, Feeney J*, Griffin RJ, Carr MD, Thomas JA, Roberts GCK, Stevens MFG. (1990). NMR studies of multiple conformations in complexes of L.casei dihydrofolate reductase with analogues of pyrimethamine. Biochemistry 29, 9660-9667.
  38. Birdsall B, Arnold JRP, Barbero JJ, Frenkiel TA, Bauer CJ, Tendler SJB, Carr MD, Thomas JA, Roberts GCK, Feeney J.* (1990). The 1H NMR assignments of the aromatic resonances in complexes of L.casei dihydrofolate reductase and the origins of their chemical shifts. Eur. J. Biochem. 191, 659-668.
  39. Carr MD, Pastore A, Gausepohl H, Frank R, Rösch P* (1990). NMR and molecular dynamics studies of the mKr2 zinc finger. Eur. J. Biochem. 188, 455-461.
  40. Carr MD, Mulvey D, Willis A, Ferguson SJ, Campbell ID* (1990). Nucleotide binding to active and 4-chloro-7-nitrobenzofurazan inhibited forms of chloroplast F1 ATPase: an NMR study. Biochem. Biophys. Acta 1015, 79-86.

Research

Structure, function and mechanism of action of proteins

I have 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. My 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 my 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 my 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, my 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 my 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).

My 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 my 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. My laboratory is 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


Current research grants

    1. UCB-Celltech Ltd Collaborative Programme Grant. High field NMR studies of protein-drug interactions. £812,434, 1.2.09-31.7.12 (a 2 year rolling research grant funded for a minimum of 3½ years
    2. MRC/UCB-Celltech Ltd Ph.D Studentship. Characterisation of the structures and interactions of cell surface receptors for Wnt family proteins. £110,720, 1.10.08-30.9.12
    3. BBSRC/UCB-Celltech Ltd Ph.D Studentship. Solution structures of complexes formed between therapeutic antibodies and target proteins. £110,720, 1.10.08-30.9.1
    4. Wellcome Trust Project Grant. Determination of the molecular basis of the cellular functions of Pdcd4, a novel type of tumour suppressor protein with key roles in the regulation of transcription and translation. £309,173, 1.12.07-30.11.10
    5. Wellcome Trust Programme Grant. Structures, functions and mechanisms of action of major M. tuberculosis and M. bovis protein virulence factors: towards a detailed understanding of the molecular basis of tuberculosis pathogenesis and importance of pathogen to host cell signalling. £494,192, 1.10.06-30.9.09 (principal applicant Dr Mark Carr and coapplicants Dr Richard Williamson, Dr Bernard Burke and Dr Stephen Gordon)
    6. BBSRC Ph.D Studentship. Determination of the roles of secreted mycobacterial proteins in pathogen to host cell signalling. £66,600, 1.10.06-30.9.10
    7. Saudi Arabia Ministry of Higher Education Ph.D Studentship. Structural and functional studies of Mycobacterium tuberculosis complex proteins linked to tuberculosis pathogenesis. £77,250, 1.10.06-30.9.09
    8. UCB-Celltech Ltd Collaborative Project Grant. High field NMR studies of protein-drug interactions. £331,184, 1.2.06-31.1.09
    9. BBSRC/UCB-Celltech Ltd Ph.D Studentship. The development and application of new NMR spectroscopy-based approaches for obtaining detailed structural and mechanistic information for novel therapeutic antibodies. £74,500, 1.10.05-31.3.09
    10. BBSRC/UCB-Celltech Ltd Ph.D Studentship. Determination of the binding site structures and mechanisms of action of therapeutic antibodies. £60,000, 1.10.05-31.1.09
    11. Iran Ministry of Health Ph.D Studentship. Determination of the structures and molecular functions of Mycobacterium tuberculosis virulence factors encoded by the Rv3613c-Rv3616c gene cluster. £64,000, 1.8.05-31.7.08

Previous research grants

I was the sole or principal applicant on all grants except for 1, 10, 12 and 13.

  1. Wellcome TrustJIF Equipment Grant. Protein structure, dynamics and interactions: 800 MHz NMR spectroscopy. £1,682,654, 1.2.02-31.10.07 (principal applicant Prof. Gordon Roberts and coapplicants Dr Mark Carr and Dr Mark Pfuhl)
  2. BBSRC Ph.D Studentship. Structural studies of complexes formed between the coactivators p300/CBP and transcription factors. £44,730, 1.10.03-30.9.06
  3. UCB-Celltech Ltd Collaborative Project Grant. High field NMR studies of protein-drug interactions. £230,543, 1.2.03-31.1.06
  4. Veterinary Laboratories Agency Ph.D Studentship. Investigation of the function and basis for antigenicity in the ESAT-6 protein family. £65,000, 1.10.02-31.3.06
  5. Wellcome Trust Project Grant. Determination of the structure and molecular function of the ESAT-6.CFP-10 complex and characterisation of the specificity of complex formation between ESAT-6/CFP-10 family proteins: towards an understanding of the roles of ESAT-6/CFP-10 in tuberculosis pathogenesis and protective immunity. £192,286, 1.10.02-31.12.05 (principal applicant Dr Mark Carr and coapplicant Dr Richard Williamson)
  6. BBSRC/Veterinary Laboratories Agency Ph.D Studentship. Structural characterisation of CFP-10 and ESAT-6: potent T-cell antigens of the M. tuberculosis complex. ~£62,500, 1.10.99-30.9.02
  7. Wellcome Trust Project Grant. Determination of the high resolution structure of the mycobacterial protein MPB70: one of the major antigenic and immunologically important proteins of both M. tuberculosis and M. bovis, the causative agents of tuberculosis. £162,263, 1.8.99-15.2.03 (principal applicant Dr Mark Carr and coapplicant Dr Richard Williamson)
  8. Celltech Ltd Ph.D Studentship. NMR-based structural analysis of the catalytic domain of one or more of the ADAMs family. £35,667, 1.11.97-31.10.00 (principal applicant Dr Mark Carr and coapplicant Dr Richard Williamson)
  9. Medical Research Council Ph.D Studentship. NMR studies of the DNA-binding domain of B-Myb. ~£45,500, 1.10.97-31.3.01
  10. Medical Research Council Project Grant. NMR-based determination of the structure of TIMP-2 and complexes formed with the catalytic domain of stromelysin. £176,922, 1.1.97-30.11.01 (principal applicant Prof. Robert Freedman and coapplicant Dr Mark Carr)
  11. Wellcome Trust Equipment Grant. NMR facility for structural studies of biomedically-significant proteins, protein-protein interactions and protein-ligand complexes. £719,208, 1.6.96-31.1.03 (principal applicant Dr Mark Carr and coapplicant Prof. Robert Freedman)
  12. Arthritis Research Campaign Research Fellowship. Molecular basis for the inhibition of matrix metalloproteinases by TIMPs. £239,792, 1.4.96-31.3.01 (principal applicant Dr Richard Williamson and coapplicants Dr Mark Carr and Prof. Robert Freedman)
  13. Medical Research Council Project Grant. Structure determination of TIMP-2 by NMR and its interaction with the catalytic domain of stromelysin. £49,680, 1.1.95-31.12.95 (principal applicant Prof. Robert Freedman and coapplicant Dr Mark Carr)
  14. Medical Research Council NMR Centre Access. NMR studies of proteins and protein-ligand complexes. Allocation of 13-18 days per year on the 600 and 800 MHz NMR spectrometers at the MRC Biomedical NMR Centre, National Institute for Medical Research, 1.1.93-31.12.04

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Redfearn Lecture 2017

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