Allosteric Pathways Originating at Cysteine Residues in Regulators of G-Protein Signaling Proteins.

Academic Article


  • 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.
  • Authors

  • Liu, Yong
  • Vashisth, Harish
  • Status

    Publication Date

  • February 2, 2021
  • Published In


  • Cysteine
  • GTP-Binding Proteins
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Digital Object Identifier (doi)

    Start Page

  • 517
  • End Page

  • 526
  • Volume

  • 120
  • Issue

  • 3