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Publication Abstract from PubMed

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-Gbetagamma complex in the presence of two of these inhibitors. Comparison with the apoGRK2-Gbetagamma structure demonstrates that the compounds bind in the kinase active site in a manner similar to the AGC kinase inhibitor balanol. Both balanol and the Takeda compounds induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homology modeling, we indentified five amino acids surrounding the inhibitor-binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.

Molecular Mechanism of Selectivity Among G Protein-Coupled Receptor Kinase 2 Inhibitors.,Thal DM, Yeow RY, Schoenau C, Huber J, Tesmer JJ Mol Pharmacol. 2011 May 19. PMID:21596927^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.