3PVU

Bovine GRK2 in complex with Gbetagamma subunits and a selective kinase inhibitor (CMPD101)

Summary for 3PVU

• Entry DOI: 10.2210/pdb3pvu/pdb
• Related: 1OMW 3CIK 3KRW 3KRX 3PSC 3PVW
• Descriptor: Beta-adrenergic receptor kinase 1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, atp-binding, inhibitor, membrane, transferase-signaling protein-inhibitor complex, transferase/signaling protein/inhibitor
• Biological source: Bos taurus (bovine); More
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side (Potential): P63212
• Total number of polymer chains: 3
• Total formula weight: 126868.87

Authors

Thal, D.M.,Tesmer, J.J. (deposition date: 2010-12-07, release date: 2011-06-01, Last modification date: 2023-09-06)

Primary citation

Thal, D.M.,Yeow, R.Y.,Schoenau, C.,Huber, J.,Tesmer, J.J.
Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors.
Mol.Pharmacol., 80:294-303, 2011

PubMed 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 demonstrates that the compounds bind in the kinase active site in a manner similar to that of 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 identified 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.

PubMed: 21596927
DOI: 10.1124/mol.111.071522

Experimental method

X-RAY DIFFRACTION (2.48 Å)