8uaq

From Proteopedia

(Difference between revisions)

Revision as of 11:48, 13 December 2023

Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL018-21

Structural highlights

8uaq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4] ^[5]

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 >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. 2023 Nov 10;264:115931. doi: 10.1016/j.ejmech.2023.115931. PMID:38016297^[6]

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

References

↑ Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Baneres JL, Benovic JL, Marin P, Bockaert J, Dumuis A. Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J. 2009 Sep 16;28(18):2706-18. Epub 2009 Aug 6. PMID:19661922 doi:http://dx.doi.org/emboj2009215
↑ Chen M, Philipp M, Wang J, Premont RT, Garrison TR, Caron MG, Lefkowitz RJ, Chen W. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem. 2009 Dec 11;284(50):35040-8. doi: 10.1074/jbc.M109.047456. Epub 2009, Oct 2. PMID:19801552 doi:10.1074/jbc.M109.047456
↑ Baameur F, Morgan DH, Yao H, Tran TM, Hammitt RA, Sabui S, McMurray JS, Lichtarge O, Clark RB. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol. 2010 Mar;77(3):405-15. doi: 10.1124/mol.109.058115. Epub 2009 Dec , 28. PMID:20038610 doi:http://dx.doi.org/10.1124/mol.109.058115
↑ Chen X, Zhu H, Yuan M, Fu J, Zhou Y, Ma L. G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J Biol Chem. 2010 Apr 23;285(17):12823-30. doi: 10.1074/jbc.M109.094243. Epub, 2010 Feb 2. PMID:20124405 doi:http://dx.doi.org/10.1074/jbc.M109.094243
↑ Barker BL, Benovic JL. G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4. Biochemistry. 2011 Aug 16;50(32):6933-41. doi: 10.1021/bi2005202. Epub 2011 Jul, 12. PMID:21728385 doi:http://dx.doi.org/10.1021/bi2005202
↑ Chen Y, Sonawane A, Manda R, Gadi RK, Tesmer JJG, Ghosh AK. 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. Eur J Med Chem. 2023 Nov 10;264:115931. PMID:38016297 doi:10.1016/j.ejmech.2023.115931

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8uaq"

Categories: Homo sapiens | Large Structures | Chen Y | Tesmer JJG

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8uaq is ON HOLD  until Paper Publication
+==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:(3Z)-N-[(1R)-1-(4-fluorophenyl)ethyl]-3-[(4-{[(2S)-2-(furan-2-yl)-2-hydroxyacetyl]amino}-3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-2,3-dihydro-1H-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.
-Authors:
+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. 2023 Nov 10;264:115931. doi: 10.1016/j.ejmech.2023.115931. PMID:38016297<ref>PMID:38016297</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</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]]

8uaq

From Proteopedia

Revision as of 11:48, 13 December 2023

Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL018-21

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox