4wbo

Bovine G Protein Coupled Receptor Kinase 1 in Complex with Amlexanox

spinqualitylabelsall models 4wbo, resolution 2.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wbo is a 4 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ANW, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GRK1_BOVIN Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade (PubMed:12686556, PubMed:16675451, PubMed:21299498). This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination (By similarity). May play a role in the maintenance of the outer nuclear layer in the retina (By similarity).[UniProtKB:Q9WVL4] Publication Abstract from PubMed G protein-coupled receptor kinases (GRKs) have been implicated in human diseases ranging from heart failure to diabetes. Previous studies have identified several compounds that selectively inhibit GRK2, such as paroxetine and balanol. Far fewer selective inhibitors have been reported for GRK5, a target for the treatment of cardiac hypertrophy, and the mechanism of action of reported compounds is unknown. To identify novel scaffolds that selectively inhibit GRK5, a differential scanning fluorometry screen was used to probe a library of 4480 compounds. The best hit was amlexanox, an FDA-approved anti-inflammatory, anti-allergic immunomodulator. The crystal structure of amlexanox in complex with GRK1 demonstrates that its tricyclic aromatic ring system forms ATP-like interactions with the hinge of the kinase domain, which is likely similar to how this drug binds to IkappaB kinase epsilon (IKKepsilon), another kinase known to be inhibited by this compound. Amlexanox was also able to inhibit myocyte enhancer factor 2 transcriptional activity in neonatal rat ventricular myocytes in a manner consistent with GRK5 inhibition. The GRK1 amlexanox structure thus serves as a springboard for the rational design of inhibitors with improved potency and selectivity for GRK5 and IKKepsilon. Identification and characterization of amlexanox as a g protein-coupled receptor kinase 5 inhibitor.,Homan KT, Wu E, Cannavo A, Koch WJ, Tesmer JJ Molecules. 2014 Oct 22;19(10):16937-49. doi: 10.3390/molecules191016937. PMID:25340299 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Rhodopsin kinase

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