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RGS inhibitors
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Rebecca Roof
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RGS (Regulators of G protein Signaling) proteins are GTPase-activating proteins (GAPs) that markedly stimulate the GTPase activity of the target Galpha subunit. Because of this activity RGS proteins reduce the signal transmitted by the receptor-activated Galpha subunit by rapidly returning it to the inactive GDP-bound state. Thus RGS proteins represent potential novel targets for therapeutic agents since the use of an RGS inhibitor simultaneously with administration of the appropriate receptor agonist could prolong or enhance the activity of drug or allow the use of a lower dosage for the similar pharmacological effect. In some cases coadministration of the receptor agonist might not even be necessary, since the increase in the basal activity of the endogenous receptor agonist could provide sufficient effect. We have used the recently reported crystal structure of the RGS4-Giα complex (1agr) to design inhibitors of RGS-Galpha complexation, based on the conformation of the Galphai segments that make contact with RGS4. A parent conformationally restrained peptide was designed from the an octapeptide fragment of the Gαi switch 1 region and was cyclized through residues 3 and 7 to maintain the binding orientation.
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RGS-inhibitor: parent peptide.
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Collaborators Involved
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Richard R. Neubig
, M.D. Ph.D. Professor of Pharmacology and Associate Professor of Internal Medicine, Department of Pharmacology UofM
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Related Publications
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Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI
Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors.
J. Pept. Res., 63: 141-146 (2004)
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Roof RA, Jin Y, Roman DL, Sunahara RK, Ishii M, Mosberg HI, Neubig RR
Mechanism of Action and Structural Requirements of Constrained Peptide Inhibitors of RGS Proteins
Chem. Biol. Drug. Des., 67: 266-274 (2006)
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Roman DL, Talbot JN, Roof RA, Sunahara RK, Traynor JR, Neubig RR
Identification of small molecule inhibitors of Regulator of G-protein Signaling 4 (RGS4) using a high throughput flow cytometry protein interaction assay (FCPIA)
Mol. Pharmacol, 71: 169-175 (2007)
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Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI
Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity.
Methods Enzymol., 389: 266-277 (2004)
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External Funding
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DA 03910, H. I. Mosberg, PI
NIH/NIDA
Conformation-Selectivity Relations of Opioid Peptides
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