Journal article
Allosteric Inhibition of the Regulator of G Protein Signaling–Gα Protein–Protein Interaction by CCG-4986
Molecular pharmacology, Vol.78(3), pp.360-365
09/2010
DOI: 10.1124/mol.109.063388
PMCID: PMC2939487
PMID: 20530129
Abstract
Regulator of G protein signaling (RGS) proteins act to temporally modulate the activity of G protein subunits after G protein-coupled receptor activation. RGS proteins exert their effect by directly binding to the activated Gα subunit of the G protein, catalyzing the accelerated hydrolysis of GTP and returning the G protein to its inactive, heterotrimeric form. In previous studies, we have sought to inhibit this GTPase-accelerating protein activity of the RGS protein by using small molecules. In this study, we investigated the mechanism of CCG-4986 [methyl-
N
-[(4-chlorophenyl)sulfonyl]-4-nitro-benzenesulfinimidoate], a previously reported small-molecule RGS inhibitor. Here, we find that CCG-4986 inhibits RGS4 function through the covalent modification of two spatially distinct cysteine residues on RGS4. We confirm that modification of Cys132, located near the RGS/Gα interaction surface, modestly inhibits Gα binding and GTPase acceleration. In addition, we report that modification of Cys148, a residue located on the opposite face of RGS4, can disrupt RGS/Gα interaction through an allosteric mechanism that almost completely inhibits the Gα–RGS protein–protein interaction. These findings demonstrate three important points: 1) the modification of the Cys148 allosteric site results in significant changes to the RGS interaction surface with Gα; 2) this identifies a “hot spot” on RGS4 for binding of small molecules and triggering an allosteric change that may be significantly more effective than targeting the actual protein-protein interaction surface; and 3) because of the modification of a positional equivalent of Cys148 in RGS8 by CCG-4986, lack of inhibition indicates that RGS proteins exhibit fundamental differences in their responses to small-molecule ligands.
Details
- Title: Subtitle
- Allosteric Inhibition of the Regulator of G Protein Signaling–Gα Protein–Protein Interaction by CCG-4986
- Creators
- David L RomanLevi L BlazerC. Aaron MonroyRichard R Neubig
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.78(3), pp.360-365
- Publisher
- The American Society for Pharmacology and Experimental Therapeutics
- DOI
- 10.1124/mol.109.063388
- PMID
- 20530129
- PMCID
- PMC2939487
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Grant note
- NS057014; DA023252; GM76821 / National Institutes of Health
- Language
- English
- Date published
- 09/2010
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984065391802771
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