View source for 8uaq


==Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL018-21==
<StructureSection load='8uaq' size='340' side='right'caption='[[8uaq]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8uaq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8UAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UAQ 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]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=W3F:(3~{Z})-~{N}-[(1~{R})-1-(4-fluorophenyl)ethyl]-3-[[4-[[(2~{S})-2-(furan-2-yl)-2-oxidanyl-ethanoyl]amino]-3,5-dimethyl-1~{H}-pyrrol-2-yl]methylidene]-2-oxidanylidene-1~{H}-indole-5-carboxamide'>W3F</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=8uaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uaq OCA], [https://pdbe.org/8uaq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uaq RCSB], [https://www.ebi.ac.uk/pdbsum/8uaq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uaq ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GRK5_HUMAN GRK5_HUMAN] Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).<ref>PMID:19661922</ref> <ref>PMID:19801552</ref> <ref>PMID:20038610</ref> <ref>PMID:20124405</ref> <ref>PMID:21728385</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC(50) value of 10 nM and exhibited &gt;100,000-fold selectivity over GRK2. The X-ray structure of a ketoamide-derived inhibitor-bound GRK5 showed the formation of a hemithioketal intermediate with active site Cys474 in the GRK5 active site and provided new insights into the ligand-binding site interactions responsible for high selectivity. The current studies serve as an important guide to therapeutic GRK5 inhibitor drug development.

Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes.,Chen Y, Sonawane A, Manda R, Gadi RK, Tesmer JJG, Ghosh AK Eur J Med Chem. 2024 Jan 15;264:115931. doi: 10.1016/j.ejmech.2023.115931. Epub , 2023 Nov 10. PMID:38016297<ref>PMID:38016297</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8uaq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen Y]]
[[Category: Tesmer JJG]]