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• W2077990714 abstract "Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations and NMR spectroscopy, we have studied in molecular detail the mechanism of action of CCG-50014, a potent small molecule inhibitor of RGS4 that covalently binds to cysteine residues on RGS4. We apply temperature-accelerated molecular dynamics (TAMD) to carry out enhanced conformational sampling of apo RGS4 structures, and consistently find that the α5-α6 helix pair of RGS4 can spontaneously span open-like conformations, allowing binding of CCG-50014 to the buried side-chain of Cys95. Both NMR experiments and MD simulations reveal chemical shift perturbations in residues in the vicinity of inhibitor binding site as well as in the RGS4-Gα binding interface. Consistent with a loss of G-protein binding, GAP activity, and allosteric mechanism of action of CCG-50014, our simulations of the RGS4-Gα complex in the presence of inhibitor suggest a relatively unstable protein-protein interaction. These results have potential implications for understanding how the conformational dynamics among RGS proteins may play a key role in the sensitivity of inhibitors." @default.
• W2077990714 created "2016-06-24" @default.
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• W2077990714 date "2013-10-24" @default.
• W2077990714 modified "2023-09-25" @default.
• W2077990714 title "Conformational Dynamics of a Regulator of G-Protein Signaling Protein Reveals a Mechanism of Allosteric Inhibition by a Small Molecule" @default.
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• W2077990714 doi "https://doi.org/10.1021/cb400568g" @default.
• W2077990714 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3876963" @default.
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• W2077990714 hasPublicationYear "2013" @default.
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