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4wbo

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Bovine G Protein Coupled Receptor Kinase 1 in Complex with Amlexanox

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.
Method:	X-ray diffraction, Resolution 2.81Å
Ligands:	,
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]^[1] ^[2] ^[3]

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^[4]

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

References

↑ Weiergraber OH, Senin II, Philippov PP, Granzin J, Koch KW. Impact of N-terminal myristoylation on the Ca2+-dependent conformational transition in recoverin. J Biol Chem. 2003 Jun 20;278(25):22972-9. Epub 2003 Apr 9. PMID:12686556 doi:10.1074/jbc.M300447200
↑ Higgins MK, Oprian DD, Schertler GF. Recoverin binds exclusively to an amphipathic peptide at the N terminus of rhodopsin kinase, inhibiting rhodopsin phosphorylation without affecting catalytic activity of the kinase. J Biol Chem. 2006 Jul 14;281(28):19426-32. doi: 10.1074/jbc.M602203200. Epub 2006 , May 4. PMID:16675451 doi:http://dx.doi.org/10.1074/jbc.M602203200
↑ Zernii EY, Komolov KE, Permyakov SE, Kolpakova T, Dell'orco D, Poetzsch A, Knyazeva EL, Grigoriev II, Permyakov EA, Senin II, Philippov PP, Koch KW. Involvement of the recoverin C-terminal segment in recognition of the target enzyme rhodopsin kinase. Biochem J. 2011 Apr 15;435(2):441-50. doi: 10.1042/BJ20110013. PMID:21299498 doi:http://dx.doi.org/10.1042/BJ20110013
↑ Homan KT, Wu E, Cannavo A, Koch WJ, Tesmer JJ. Identification and characterization of amlexanox as a g protein-coupled receptor kinase 5 inhibitor. Molecules. 2014 Oct 22;19(10):16937-49. doi: 10.3390/molecules191016937. PMID:25340299 doi:http://dx.doi.org/10.3390/molecules191016937

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4wbo"

Categories: Bos taurus | Large Structures | Homan KT | Tesmer JJG

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4wbo]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WBO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANW:2-AMINO-7-(1-METHYLETHYL)-5-OXO-5H-CHROMENO[2,3-B]PYRIDINE-3-CARBOXYLIC+ACID'>ANW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.81&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANW:2-AMINO-7-(1-METHYLETHYL)-5-OXO-5H-CHROMENO[2,3-B]PYRIDINE-3-CARBOXYLIC+ACID'>ANW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4wbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wbo OCA], [https://pdbe.org/4wbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wbo RCSB], [https://www.ebi.ac.uk/pdbsum/4wbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wbo ProSAT]</span></td></tr>
 </table>

4wbo

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Current revision

Bovine G Protein Coupled Receptor Kinase 1 in Complex with Amlexanox

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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