G protein-coupled receptor (GPCR) kinases (GRKs) recognize and phosphorylate activated GPCRs, initiating the process by which they are desensitized. Recent advances have shed knew light on the mechanism by which GRKs are allosterically regulated by GPCRs. Aiding these studies have been atomic structures of GRKs in complex with small molecule inhibitors, which have not only trapped GRKs in unanticipated conformations, but also provided new ideas for the development of selective drugs. Herein we describe the current model for GRK activation and a chemical genomics screen that identified a selective serotonin reuptake inhibitor as an inhibitor of GRK2 both in vitro and in living cells. The inhibitor stabilizes a unique conformation of the kinase domain that involves residues unique to GRK2. The structure of its complex represents a useful starting point for the rational design of GRK2-selective drugs that could used to treat heart failure and other cardiovascular diseases.

G protein-coupled receptor kinases: Molecular mechanism and inhibition

244th National Meeting (2012)

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