6c2y
From Proteopedia
Human GRK2 in complex with Gbetagamma subunits and CCG257142
Structural highlights
FunctionARBK1_HUMAN 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.[1] Publication Abstract from PubMedG protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2-Gbetagamma.GSK180736A and GRK5.CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2. Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors.,Waldschmidt HV, Bouley R, Kirchhoff PD, Lee P, Tesmer JJG, Larsen SD Bioorg Med Chem Lett. 2018 May 15;28(9):1507-1515. doi:, 10.1016/j.bmcl.2018.03.082. Epub 2018 Mar 30. PMID:29627263[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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