Research in this laboratory 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 on the development and application of novel NMR and computational methods to aid in these studies.Over the last year we have developed novel hybrid methods combining NMR and solution scattering to solve the structures of proteins and proetin complexes in excess of 100 kDa. Structures that have been solved this year include the 128 kDa enzyme I and its 146 kDa complex with HPr from the bacterial phosphotransferase system (PTS), and the complex of IIAchitobiose with IIBchitobiose, also from the PTS. In addition, we have devoted significant efforts towards detecting, characterizing and visualizing highly transient, lowly-populated states that are invisible to conventional biophysical and structural techniques, yet play a key role in numerous biological processes including recognition, allostery, signal transduction, etc.... by means of paramagnetic relaxation enhancement (PRE) and novel relaxation methods. Using these approaches we have been able to characterize sliding and hopping of a multidomain transcription factor on NDA, to characteristics the mechanistic details involving encounter complex formation in protein-protein interactions, and to study the exchange between monomeric and protofibril forms of amyloid Abeta.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2012
Total Cost
$2,395,557
Indirect Cost
City
State
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Zip Code
Ceccon, Alberto; Schmidt, Thomas; Tugarinov, Vitali et al. (2018) Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR. J Am Chem Soc 140:6199-6202
Deshmukh, Lalit; Tugarinov, Vitali; Appella, Daniel H et al. (2018) Targeting a Dark Excited State of HIV-1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy. Angew Chem Int Ed Engl 57:2687-2691
Wälti, Marielle A; Libich, David S; Clore, G Marius (2018) Extensive Sampling of the Cavity of the GroEL Nanomachine by Protein Substrates Probed by Paramagnetic Relaxation Enhancement. J Phys Chem Lett 9:3368-3371
Schmidt, Thomas; Tian, Lan; Clore, G Marius (2018) Probing Conformational States of the Finger and Thumb Subdomains of HIV-1 Reverse Transcriptase Using Double Electron-Electron Resonance Electron Paramagnetic Resonance Spectroscopy. Biochemistry 57:489-493
Wälti, Marielle A; Clore, G Marius (2018) Disassembly/reassembly strategy for the production of highly pure GroEL, a tetradecameric supramolecular machine, suitable for quantitative NMR, EPR and mutational studies. Protein Expr Purif 142:8-15
Wälti, Marielle A; Schmidt, Thomas; Murray, Dylan T et al. (2017) Chaperonin GroEL accelerates protofibril formation and decorates fibrils of the Het-s prion protein. Proc Natl Acad Sci U S A 114:9104-9109
Ceccon, Alberto; Tugarinov, Vitali; Boughton, Andrew J et al. (2017) Probing the Binding Modes of a Multidomain Protein to Lipid-based Nanoparticles by Relaxation-based NMR. J Phys Chem Lett 8:2535-2540
Schwieters, Charles D; Bermejo, Guillermo A; Clore, G Marius (2017) Xplor-NIH for Molecular Structure Determination from NMR and Other Data Sources. Protein Sci :
Libich, David S; Tugarinov, Vitali; Ghirlando, Rodolfo et al. (2017) Confinement and Stabilization of Fyn SH3 Folding Intermediate Mimetics within the Cavity of the Chaperonin GroEL Demonstrated by Relaxation-Based NMR. Biochemistry 56:903-906
Deshmukh, Lalit; Tugarinov, Vitali; Louis, John M et al. (2017) Binding kinetics and substrate selectivity in HIV-1 protease-Gag interactions probed at atomic resolution by chemical exchange NMR. Proc Natl Acad Sci U S A 114:E9855-E9862

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