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Regulators of G‐protein Signaling Proteins: Conformational Dynamics and Allosteric Control
Author(s) -
VASHISTH HARISH
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.881.16
Subject(s) - allosteric regulation , g protein coupled receptor , small molecule , chemistry , g protein , gtpase activating protein , biophysics , allosteric enzyme , cysteine , signaling proteins , microbiology and biotechnology , biochemistry , signal transduction , receptor , biology , enzyme
Regulators of G‐protein signaling (RGS) proteins are intracellular proteins that negatively modulate the signaling pathways of G‐protein coupled receptors (GPCRs). Because RGS proteins directly bind to activated G‐proteins and accelerate the rate of GTP‐hydrolysis, they have emerged as potential drug targets for regulating GPCR signaling. While conventional approaches have been focused on directly targeting RGS‐Gα protein‐protein interaction using small molecules, new approaches that target allosteric sites are emerging. In this work, we have studied using atomistic simulations the mechanism of action of a small molecule that binds, with differing affinity, to specific cysteine residues on two structurally homologous RGS proteins, RGS4 and RGS8. We find that each RGS protein has flexibility in a pair of helices that allows small molecule to access buried cysteine residues. Such flexibility only became apparent on application of enhanced sampling simulations on apo‐RGS structures. Moreover, we observe that the small molecule can spontaneously bind to “conformationally‐open” RGS proteins, but only associates with different surface sites in “conformationally‐closed” RGS proteins. The binding of small molecule to a buried cysteine residue on each protein also appears to perturb the protein‐protein interface in each RGS‐Gα complex via an allosteric mechanism.