Work in this laboratory has been focussed on the determination of three-dimensional structures of larger proteins in solution by NMR, with a particular emphasis on cytokines, immune related proteins, DNA-protein complexes, and protein-protein complexes. A considerable effort has been placed on the development of three- and four-dimensional heteronuclear NMR to extend the application of NMR as a method for determining three-dimensional structures of proteins in solution beyond the limits of conventional two-dimensional NMR (about 100 residues) to molecules in the 150- to 400-residue range. High resolution solution structures of a number proteins have been determined. These include the oligomerization domain of p53, the beta chemokine macrophage inflammatory protein-1-beta (hMIP-1-beta), oxidized and reduced human thioredoxin, and the trypsin inhibitor of Ascaris. Extensive use in these studies has been made of multi-dimensional heteronuclear NMR and of systematic conformational searches to obtain stereospecific assignments and torsion angle restraints which have enabled us to obtain very high resolution structures comparable in accuracy to 2 Angstroms resolution X-ray structures. The typical accuracy attainable is 0.2-0.4 Angstroms for the backbone atoms and 0.3-0.5 Angstroms for the internal side chains.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
City
State
Country
United States
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Venditti, Vincenzo; Ghirlando, Rodolfo; Clore, G Marius (2013) Structural basis for enzyme I inhibition by ?-ketoglutarate. ACS Chem Biol 8:1232-40
Grishaev, Alexander; Anthis, Nicholas J; Clore, G Marius (2012) Contrast-matched small-angle X-ray scattering from a heavy-atom-labeled protein in structure determination: application to a lead-substituted calmodulin-peptide complex. J Am Chem Soc 134:14686-9
Iwahara, Junji; Tang, Chun; Marius Clore, G (2007) Practical aspects of (1)H transverse paramagnetic relaxation enhancement measurements on macromolecules. J Magn Reson 184:185-95
Clore, G Marius; Tang, Chun; Iwahara, Junji (2007) Elucidating transient macromolecular interactions using paramagnetic relaxation enhancement. Curr Opin Struct Biol 17:603-16
Tang, Chun; Schwieters, Charles D; Clore, G Marius (2007) Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR. Nature 449:1078-82
Cai, Mengli; Huang, Ying; Suh, Jeong-Yong et al. (2007) Solution NMR structure of the barrier-to-autointegration factor-Emerin complex. J Biol Chem 282:14525-35
Schwieters, Charles D; Clore, G Marius (2007) 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
Hu, Kaifeng; Vogeli, Beat; Clore, G Marius (2007) 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
Suh, Jeong-Yong; Iwahara, Junji; Clore, G Marius (2007) 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
Iwahara, Junji; Jung, Young-Sang; Clore, G Marius (2007) Heteronuclear NMR spectroscopy for lysine NH(3) groups in proteins: unique effect of water exchange on (15)N transverse relaxation. J Am Chem Soc 129:2971-80

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