Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity.
One of the principal roles of the multifunctional regulator of G-protein signaling (RGS) proteins is to terminate G-protein-coupled receptor (GPCR) signaling by binding to the G-protein Galpha subunit, thus acting as GTPase-activating proteins (GAPs). In principle, then, selective inhibitors of this GAP function would have potential as therapeutic agents, as they could be used to augment the effects of endogenous or exogenous GPCR agonists. Using the published RGS4-G(ialpha1) X-ray structure, we have designed and synthesized a series of cyclic peptides, modeled on the G(ialpha) switch I region, that inhibit RGS4 GAP activity, presumably by blocking the interaction between RGS4 and G(ialpha1). These compounds should prove useful for elucidating RGS-mediated activity and serve as a starting point for the development of a novel class of therapeutic agent.
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109, USA
Yafei
Y
Jin
Huailing
H
Zhong
John R
JR
Omnaas
Richard R
RR
Neubig
Henry I
HI
Mosberg
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D020690:GTPase-Activating Proteins / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020710:RGS Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D020690:GTPase-Activating Proteins; D010456:Peptides, Cyclic; D020710:RGS Proteins; C098799:RGS4 protein; D003545:Cysteine