G. Marius Clore, M.D., Ph.D. : NIDDK

G. Marius Clore, M.D., Ph.D.

NIDDK, National Institutes of Health
Building 5, Room B130
5 Memorial Dr.
Bethesda, MD 20892-0520
Tel: 301-496-0782
Fax: 301-496-0825
Email: mariusc@intra.niddk.nih.gov

Research Website:

Education / Previous Training and Experience:
B.Sc., University College, London, 1976
M.D., University College Hospital Medical School, London, 1979
Ph.D., National Institute for Medical Research, London, 1982

Research Statement:

Current research is centered around solution studies on the structure and dynamics of proteins, protein-protein complexes and protein-nucleic acid complexes using multidimensional NMR spectroscopy, and the development and application of novel NMR and computational methods to aid in these studies. Particular emphasis is being placed on complexes involved in signal transduction and transcriptional regulation, and on AIDS and AIDS-related proteins.

Recent accomplishments include the extension of the applicability of the NMR method to structures larger than 40 kDa, including the determination of the three-dimensional solution structures of the complete 44 kDa trimeric ectodomain of SIV gp41, the 42 kDa ternary Oct1/SOx2/Hoxb1-DNA transcription factor complex, and the 40 kDa phosphoryl transfer complex of enzyme I and the histidine-containing phosphocarrier protein (HPr) of the bacterial PTS system. Other systems whose structures have recently been solved include: a number of other complexes from the bacterial PTS system including complexes of enzyme IIAGlc with HPr and the IIB domain of enzyme IICBGlc, and a complex of enzyme IIAMtl with HPr; complexes of the transcription factors GATA-1, AREA, HMG-I/Y, and MEF2A with DNA, complexes of wild-type SRY (the mammalian male sex determining factor) and a sex reversal mutant of SRY with double stranded DNA; a 35 kDa complex of FBP with single stranded DNA; the anti-HIV protein cyanovirin in monomeric and domain-swapped dimeric forms, the cellular factor BAF that is responsible for protecting retroviral DNA from autointegration, and the N- and C-terminal domains of HIV integrase.

Examples of methodological developments include the panoply of 3D and 4D heteronuclear NMR experiments that have been developed at NIH and are essential for studying larger proteins where overlapping resonances pose a formidable problem; methods that make use of anisotropy of the alignment tensor (e.g., residual dipolar couplings measured on macromolecules dissolved in dilute liquid crystalline media such as the nematic phases of rod-shaped charged virus particles) or the diffusion tensor (for highly non-spherical macromolecules) to provide long-range structural information that is not available from other NMR parameters that rely entirely on close spatial proximity of atoms; and the development of fast and efficient algorithms for the analysis of NMR spectra and for the computation of three-dimensional structures based on all available experimental NMR restraints.

Selected Publications:

1. Gustchina E, Louis JM, Lam SN, Bewley CA, Clore GM A monoclonal Fab derived from a human nonimmune phage library reveals a new epitope on gp41 and neutralizes diverse human immunodeficiency virus type 1 strains. J Virol(81): 12946-53, 2007. [Full Text/Abstract]

2. Schwieters CD, Clore GM A physical picture of atomic motions within the Dickerson DNA dodecamer in solution derived from joint ensemble refinement against NMR and large-angle X-ray scattering data. Biochemistry(46): 1152-66, 2007. [Full Text/Abstract]

3. Clore GM, Tang C, Iwahara J Elucidating transient macromolecular interactions using paramagnetic relaxation enhancement. Curr Opin Struct Biol(17): 603-16, 2007. [Full Text/Abstract]

4. Iwahara J, Jung YS, Clore GM Heteronuclear NMR Spectroscopy for Lysine NH(3) Groups in Proteins: Unique Effect of Water Exchange on (15)N Transverse Relaxation. J Am Chem Soc , 2007. [Full Text/Abstract]

5. Suh JY, Iwahara J, Clore GM Intramolecular domain-domain association/dissociation and phosphoryl transfer in the mannitol transporter of Escherichia coli are not coupled. Proc Natl Acad Sci U S A(104): 3153-8, 2007. [Full Text/Abstract]

6. Suh JY, Iwahara J, Clore GM Intramolecular domain-domain association/dissociation and phosphoryl transfer in the mannitol transporter of Escherichia coli are not coupled. Proc Natl Acad Sci U S A(104): 3153-8, 2007. [Full Text/Abstract]

7. Tang C, Schwieters CD, Clore GM Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR. Nature(449): 1078-82, 2007. [Full Text/Abstract]

8. Suh JY, Tang C, Clore GM Role of electrostatic interactions in transient encounter complexes in protein-protein association investigated by paramagnetic relaxation enhancement. J Am Chem Soc(129): 12954-5, 2007. [Full Text/Abstract]

9. Cai M, Huang Y, Suh JY, Louis JM, Ghirlando R, Craigie R, Clore GM Solution NMR structure of the barrier-to-autointegration factor-Emerin complex. J Biol Chem(282): 14525-35, 2007. [Full Text/Abstract]

10. Hu K, Vögeli B, Clore GM Spin-state selective carbon-detected HNCO with TROSY optimization in all dimensions and double echo-antiecho sensitivity enhancement in both indirect dimensions. J Am Chem Soc(129): 5484-91, 2007. [Full Text/Abstract]

11. Sahu D, Clore GM, Iwahara J TROSY-based z-exchange spectroscopy: application to the determination of the activation energy for intermolecular protein translocation between specific sites on different DNA molecules. J Am Chem Soc(129): 13232-7, 2007. [Full Text/Abstract]

12. Clore GM, Schwieters CD Concordance of residual dipolar couplings, backbone order parameters and crystallographic B-factors for a small alpha/beta protein: a unified picture of high probability, fast atomic motions in proteins. J Mol Biol (355): 879-86, 2006. [Full Text/Abstract]

13. Iwahara J, Clore GM Detecting transient intermediates in macromolecular binding by paramagnetic NMR. Nature (440): 1227-30, 2006. [Full Text/Abstract]

14. Iwahara J, Clore GM Direct observation of enhanced translocation of a homeodomain between DNA cognate sites by NMR exchange spectroscopy. J Am Chem Soc (128): 404-5, 2006. [Full Text/Abstract]

15. Iwahara J, Zweckstetter M, Clore GM NMR structural and kinetic characterization of a homeodomain diffusing and hopping on nonspecific DNA. Proc Natl Acad Sci U S A (103): 15062-7, 2006. [Full Text/Abstract]

16. Suh JY, Cai M, Williams DC Jr, Clore GM Solution structure of a post-transition state analog of the phosphotransfer reaction between the A and B cytoplasmic domains of the mannitol transporter IIMannitol of the Escherichia coli phosphotransferase system. J Biol Chem (281): 8939-49, 2006. [Full Text/Abstract]

17. Gustchina E, Louis JM, Bewley CA, Clore GM Synergistic inhibition of HIV-1 envelope-mediated membrane fusion by inhibitors targeting the N and C-terminal heptad repeats of gp41. J Mol Biol (364): 283-9, 2006. [Full Text/Abstract]

18. Tang C, Iwahara J, Clore GM Visualization of transient encounter complexes in protein-protein association. Nature (444): 383-6, 2006. [Full Text/Abstract]

19. Louis JM, Bewley CA, Gustchina E, Aniana A, Clore GM Characterization and HIV-1 fusion inhibitory properties of monoclonal Fabs obtained from a human non-immune phage library selected against diverse epitopes of the ectodomain of HIV-1 gp41. J Mol Biol (353): 945-51, 2005. [Full Text/Abstract]

20. Williams DC Jr, Lee JY, Cai M, Bewley CA, Clore GM Crystal structures of the HIV-1 inhibitory cyanobacterial protein MVL free and bound to Man3GlcNAc2: structural basis for specificity and high-affinity binding to the core pentasaccharide from n-linked oligomannoside. J Biol Chem (280): 29269-76, 2005. [Full Text/Abstract]

21. Gustchina E, Hummer G, Bewley CA, Clore GM Differential inhibition of HIV-1 and SIV envelope-mediated cell fusion by C34 peptides derived from the C-terminal heptad repeat of gp41 from diverse strains of HIV-1, HIV-2, and SIV. J Med Chem (48): 3036-44, 2005. [Full Text/Abstract]

22. Williams DC Jr, Cai M, Suh JY, Peterkofsky A, Clore GM Solution NMR structure of the 48-kDa IIAMannose-HPr complex of the Escherichia coli mannose phosphotransferase system. J Biol Chem (280): 20775-84, 2005. [Full Text/Abstract]

23. Tang C, Williams DC Jr, Ghirlando R, Clore GM Solution structure of enzyme IIA(Chitobiose) from the N,N''-diacetylchitobiose branch of the Escherichia coli phosphotransferase system. J Biol Chem (280): 11770-80, 2005. [Full Text/Abstract]

24. Clore GM, Schwieters CD Amplitudes of protein backbone dynamics and correlated motions in a small alpha/beta protein: correspondence of dipolar coupling and heteronuclear relaxation measurements. Biochemistry (43): 10678-91, 2004. [Full Text/Abstract]

25. Iwahara J, Schwieters CD, Clore GM Characterization of nonspecific protein-DNA interactions by 1H paramagnetic relaxation enhancement. J Am Chem Soc (126): 12800-8, 2004. [Full Text/Abstract]

26. Kuszewski J Schwieters CD Garrett DS Byrd RA Tjandra N Clore GM Completely automated, highly error-tolerant macromolecular structure determination from multidimensional nuclear overhauser enhancement spectra and chemical shift assignments. J Am Chem Soc (126): 6258-73, 2004. [Full Text/Abstract]

27. Iwahara J Schwieters CD Clore GM Ensemble approach for NMR structure refinement against (1)H paramagnetic relaxation enhancement data arising from a flexible paramagnetic group attached to a macromolecule. J Am Chem Soc (126): 5879-96, 2004. [Full Text/Abstract]

28. Clore GM Schwieters CD How much backbone motion in ubiquitin is required to account for dipolar coupling data measured in multiple alignment media as assessed by independent cross-validation? J Am Chem Soc (126): 2923-38, 2004. [Full Text/Abstract]

29. Williams DC Jr Cai M Clore GM Molecular basis for synergistic transcriptional activation by Oct1 and Sox2 revealed from the solution structure of the 42-kDa Oct1.Sox2.Hoxb1-DNA ternary transcription factor complex. J Biol Chem (279): 1449-57, 2004. [Full Text/Abstract]

30. Legler PM, Cai M, Peterkofsky A, Clore GM Three-dimensional solution structure of the cytoplasmic B domain of the mannitol transporter IImannitol of the Escherichia coli phosphotransferase system. J Biol Chem (279): 39115-21, 2004. [Full Text/Abstract]

31. Louis JM Nesheiwat I Chang L Clore GM Bewley CA Covalent trimers of the internal N-terminal trimeric coiled-coil of gp41 and antibodies directed against them are potent inhibitors of HIV envelope-mediated cell fusion. J Biol Chem (278): 20278-85, 2003. [Full Text/Abstract]

32. Clore GM Schwieters CD Docking of protein-protein complexes on the basis of highly ambiguous intermolecular distance restraints derived from 1H/15N chemical shift mapping and backbone 15N-1H residual dipolar couplings using conjoined rigid body/torsion angle dynamics. J Am Chem Soc (125): 2902-12, 2003. [Full Text/Abstract]

33. Iwahara J, Anderson DE, Murphy EC, Clore GM EDTA-derivatized deoxythymidine as a tool for rapid determination of protein binding polarity to DNA by intermolecular paramagnetic relaxation enhancement. J Am Chem Soc (125): 6634-5, 2003. [Full Text/Abstract]

34. Cai M Williams DC Jr Wang G Lee BR Peterkofsky A Clore GM Solution structure of the phosphoryl transfer complex between the signal-transducing protein IIAGlucose and the cytoplasmic domain of the glucose transporter IICBGlucose of the Escherichia coli glucose phosphotransferase system. J Biol Chem (278): 25191-206, 2003. [Full Text/Abstract]

35. Schwieters CD Kuszewski JJ Tjandra N Marius Clore G The Xplor-NIH NMR molecular structure determination package. J Magn Reson (160): 65-73, 2003. [Full Text/Abstract]

36. Bewley CA Louis JM Ghirlando R Clore GM Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41. J Biol Chem (277): 14238-45, 2002. [Full Text/Abstract]

37. Cornilescu G Lee BR Cornilescu CC Wang G Peterkofsky A Clore GM Solution structure of the phosphoryl transfer complex between the cytoplasmic A domain of the mannitol transporter IIMannitol and HPr of the Escherichia coli phosphotransferase system. J Biol Chem (277): 42289-98, 2002. [Full Text/Abstract]

38. Braddock DT Louis JM Baber JL Levens D Clore GM Structure and dynamics of KH domains from FBP bound to single-stranded DNA. Nature (415): 1051-6, 2002. [Full Text/Abstract]

39. Louis JM Bewley CA Clore GM Design and properties of N(CCG)-gp41, a chimeric gp41 molecule with nanomolar HIV fusion inhibitory activity. J Biol Chem (276): 29485-9, 2001. [Full Text/Abstract]

40. Schwieters CD Clore GM Internal coordinates for molecular dynamics and minimization in structure determination and refinement. J Magn Reson (152): 288-302, 2001. [Full Text/Abstract]

41. Murphy EC Zhurkin VB Louis JM Cornilescu G Clore GM Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol (312): 481-99, 2001. [Full Text/Abstract]

42. Clore GM. Accurate and rapid docking of protein-protein complexes on the basis of intermolecular nuclear Overhauser enhancement data and dipolar couplings by rigid body minimization. Proceedings of the National Academy of Sciences of the United States of America (97): 9021-9025, 2000.

43. Bewley CA, Clore GM. Determination of the relative orientation of the two halves of the domain-swapped dimer of cyanovirin-N in solution using dipolar couplings and rigid body minimization. Journal of the American Chemistry Society(122): 6009-6016, 2000.

44. Huang K Louis JM Donaldson L Lim FL Sharrocks AD Clore GM Solution structure of the MEF2A-DNA complex: structural basis for the modulation of DNA bending and specificity by MADS-box transcription factors. EMBO J (19): 2615-28, 2000. [Full Text/Abstract]

45. Wang G Louis JM Sondej M Seok YJ Peterkofsky A Clore GM Solution structure of the phosphoryl transfer complex between the signal transducing proteins HPr and IIA(glucose) of the Escherichia coli phosphoenolpyruvate:sugar phosphotransferase system. EMBO J (19): 5635-49, 2000. [Full Text/Abstract]

46. Garrett DS Seok YJ Peterkofsky A Gronenborn AM Clore GM Solution structure of the 40,000 Mr phosphoryl transfer complex between the N-terminal domain of enzyme I and HPr. Nat Struct Biol (6): 166-73, 1999. [Full Text/Abstract]

47. Caffrey M Cai M Kaufman J Stahl SJ Wingfield PT Covell DG Gronenborn AM Clore GM Three-dimensional solution structure of the 44 kDa ectodomain of SIV gp41. EMBO J (17): 4572-84, 1998. [Full Text/Abstract]

Page last updated: December 15, 2008

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