View source for 4pnk


==G protein-coupled receptor kinase 2 in complex with GSK180736A==
<StructureSection load='4pnk' size='340' side='right'caption='[[4pnk]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4pnk]] 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=4PNK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PNK 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]] 2.56&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KZQ:(4S)-4-(4-FLUOROPHENYL)-N-(2H-INDAZOL-5-YL)-6-METHYL-2-OXO-1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARBOXAMIDE'>KZQ</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=4pnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pnk OCA], [https://pdbe.org/4pnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pnk RCSB], [https://www.ebi.ac.uk/pdbsum/4pnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pnk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_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.<ref>PMID:19306925</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson's disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 A spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.

Identification and Structure-Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors.,Homan KT, Larimore KM, Elkins JM, Szklarz M, Knapp S, Tesmer JJ ACS Chem Biol. 2014 Oct 3. PMID:25238254<ref>PMID:25238254</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4pnk" 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: Elkins J]]
[[Category: Homan KT]]
[[Category: Knapp S]]
[[Category: Larimore KM]]
[[Category: Tesmer JJG]]