3psc | pdb_00003psc

Bovine GRK2 in complex with Gbetagamma subunits

spinqualitylabelsall models 3psc, resolution 2.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3psc is a 3 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.67Å Ligands: CMT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ARBK1_BOVIN Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (By similarity). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta adrenergic receptor kinase 3D structures Transducin 3D structures

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