Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors.

ABSTRACT: G protein-coupled receptors (GPCRs) are key regulators of cell physiology and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compounds developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we determined crystal structures of the bovine GRK2-Gβγ complex in the presence of two of these inhibitors. Comparison with the apoGRK2-Gβγ structure demonstr

SUBMITTER: Thal DM 

PROVIDER: S-EPMC3141885 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature