Allosteric Pathways Originating at Cysteine Residues in Regulators of G-Protein Signaling Proteins
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Regulators of G-protein signaling (RGS) proteins play a central role in modulating signaling via G-protein coupled receptors (GPCRs). Specifically, RGS proteins bind to activated Gα subunits in G-proteins, accelerate the GTP hydrolysis, and thereby rapidly dampen GPCR signaling. Therefore, covalent molecules targeting conserved cysteine residues among RGS proteins have emerged as potential candidates to inhibit the RGS/Gα protein-protein interaction and enhance GPCR signaling. Although these inhibitors bind to conserved cysteine residues among RGS proteins, we have previously suggested [J. Am. Chem. Soc. 2018;140:3454–3460] that their potencies and specificities are related to differential protein dynamics among RGS proteins. Using data from all-atom molecular dynamics simulations, we reveal these differences in dynamics of RGS proteins by partitioning the protein structural space into a network of communities that allow allosteric signals to propagate along unique pathways originating at inhibitor binding sites and terminating at the RGS/Gα protein-protein interface.
Digital Object Identifier (DOI)
Yong Liu, Harish Vashisth, Allosteric Pathways Originating at Cysteine Residues in Regulators of G-Protein Signaling Proteins, Biophysical Journal, Volume 120, Issue 3, 2021, Pages 517-526, ISSN 0006-3495, https://doi.org/10.1016/j.bpj.2020.12.010.