View source for 5ukm


==bovine GRK2 in complex with human Gbetagamma subunits and CCG258208 (14as)==
<StructureSection load='5ukm' size='340' side='right'caption='[[5ukm]], [[Resolution|resolution]] 3.03&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ukm]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UKM FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.03&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CMT:O-METHYLCYSTEINE'>CMT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=T0E:5-[(3S,4R)-3-{[(2H-1,3-BENZODIOXOL-5-YL)OXY]METHYL}PIPERIDIN-4-YL]-2-FLUORO-N-[(1H-PYRAZOL-5-YL)METHYL]BENZAMIDE'>T0E</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=5ukm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ukm OCA], [https://pdbe.org/5ukm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ukm RCSB], [https://www.ebi.ac.uk/pdbsum/5ukm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ukm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ARBK1_BOVIN 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).
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== Publication Abstract from PubMed ==
In heart failure, the beta-adrenergic receptors (betaARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases. Furthermore, 14as showed a 100-fold improvement in cardiomyocyte contractility assays over paroxetine and a plasma concentration higher than its IC50 for over 7 h. Three of these inhibitors, including 14as, were additionally crystallized in complex with GRK2 to give insights into the structural determinants of potency and selectivity of these inhibitors.

Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.,Waldschmidt HV, Homan KT, Cato MC, Cruz-Rodriguez O, Cannavo A, Wilson MW, Song J, Cheung JY, Koch WJ, Tesmer JJ, Larsen SD J Med Chem. 2017 Mar 29. doi: 10.1021/acs.jmedchem.7b00112. PMID:28323425<ref>PMID:28323425</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ukm" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta adrenergic receptor kinase 3D structures|Beta adrenergic receptor kinase 3D structures]]
*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cruz-Rodriguez O]]
[[Category: Tesmer JJG]]