RGD Reference Report - Allosteric inhibition of the regulator of G protein signaling-Galpha protein-protein interaction by CCG-4986. - Rat Genome Database

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Allosteric inhibition of the regulator of G protein signaling-Galpha protein-protein interaction by CCG-4986.

Authors: Roman, DL  Blazer, LL  Monroy, CA  Neubig, RR 
Citation: Roman DL, etal., Mol Pharmacol. 2010 Sep;78(3):360-5. doi: 10.1124/mol.109.063388. Epub 2010 Jun 7.
RGD ID: 7207369
Pubmed: PMID:20530129   (View Abstract at PubMed)
PMCID: PMC2939487   (View Article at PubMed Central)
DOI: DOI:10.1124/mol.109.063388   (Journal Full-text)

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 Galpha 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/Galpha interaction surface, modestly inhibits Galpha binding and GTPase acceleration. In addition, we report that modification of Cys148, a residue located on the opposite face of RGS4, can disrupt RGS/Galpha interaction through an allosteric mechanism that almost completely inhibits the Galpha-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 Galpha; 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rgs4Ratpositive regulation of GTPase activity  IMP  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rgs4RatG-protein alpha-subunit binding  IPIGnao1 (Rattus norvegicus) RGD 
Gnao1RatGTPase activating protein binding  IPIRgs4 (Rattus norvegicus) RGD 
Rgs4RatGTPase activator activity  IMP  RGD 
Gnao1RatGTPase activity  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gnao1  (G protein subunit alpha o1)
Rgs4  (regulator of G-protein signaling 4)


Additional Information