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J. Biol. Chem., Vol. 277, Issue 9, 6767-6770, March 1, 2002

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ACCELERATED PUBLICATION
Identification of Structural Features in the G-protein Regulatory Motif Required for Regulation of Heterotrimeric G-proteins^*

Yuri K. Peterson, Starr Hazard III, Stephen G. Graber^§, and Stephen M. Lanier^¶

From the Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, New Orleans, Louisiana 70118, the  Department of Library and Informatics, Medical University of South Carolina, Charleston, South Carolina 29425, and the ^§ Department of Biochemistry and Molecular Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26506

The G-protein regulatory (GPR) motif, a conserved 25-30 amino acid domain found in multiple mammalian proteins, stabilizes the GDP-bound conformation of G_i, inhibits guanosine 5'-O-(3-thiotriphosphate) (GTPS) binding to G_i and competes for G binding to G. To define the core GPR motif and key amino acid residues within a GPR peptide (TMGEEDFFDLLAKSQSKRMDDQRVDLAG), we determined the effect of truncation, insertion, and alanine substitutions on peptide-mediated inhibition of GTPS binding to purified G_i1. The bioactive core GPR peptide consists of 17 amino acids (⁷F-R²³). Within this core motif, two hydrophobic sectors (⁷FF⁸ and ¹⁰LL¹¹) and Q²² are required for bioactivity, whereas M19A and R23A increased IC₅₀ values by 70-fold. Disruption of spatial relationships between the required sectors in the amino and carboxyl regions of the peptide also resulted in a loss of biological activity. Mutation of three charged sectors (⁴EED⁶, R¹⁸, ²⁰DD²¹) within the 28-amino acid GPR decreased peptide affinity by ~10-fold. Alanine substitutions of selected residues within the core GPR peptide differently influenced peptide inhibition of GTPS binding to G_i versus G_o. These data provide a platform for the development of novel, G-protein-selective therapeutics that inhibit G_i-mediated signaling, selectively activate G-sensitive effectors, and/or disrupt specific regulatory input to G-proteins mediated by GPR-containing proteins.

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