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Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Galpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Galpha, RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Galpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Galpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Galpha substrate, suggests that unique structural determinants specific to particular RGS protein/Galpha pairings exist and could be used to achieve selective inhibition by small molecules.

Original publication

DOI

10.1073/pnas.0801508105

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

23/04/2008

Volume

105

Pages

6457 - 6462

Addresses

Structural Genomics Consortium, Oxford University, Oxford OX3 7DQ, United Kingdom.

Keywords

Humans, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, RGS Proteins, Apoproteins, Protein Subunits, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Binding, Models, Molecular