9bre: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 9bre is ~~ON HOLD until Paper~~ Publication

==Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL019-21==

== Structural highlights ==

<table><tr><td colspan='2'>[[9bre]] 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=9BRE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BRE 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]] 2.8Å</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=9bre FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9bre OCA], [https://pdbe.org/9bre PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9bre RCSB], [https://www.ebi.ac.uk/pdbsum/9bre PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9bre 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>

== Publication Abstract from PubMed ==

G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.

~~Authors:~~ Chen, Y., Tesmer, J.J.G.

Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors.,Ghosh AK, Chen Y, Gadi RK, Sonawane A, Gamage SP, Tesmer JG Eur J Med Chem. 2025 Jan 15;282:117024. doi: 10.1016/j.ejmech.2024.117024. Epub , 2024 Nov 8. PMID:39549325<ref>PMID:39549325</ref>

~~Description: Crystal Structure~~ of ~~Human G Protein~~-~~Coupled Receptor Kinase 5 in Complex with GRL019~~-21

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

[[Category: ~~Unreleased Structures~~]]

</div>

[[Category: ~~Tesmer, J.J.G~~]]

[[Category: Chen, Y]]

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Chen Y]]

[[Category: Tesmer JJG]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9bre is ON HOLD  until Paper Publication
+==Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL019-21==
+<StructureSection load='9bre' size='340' side='right'caption='[[9bre]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9bre]] 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=9BRE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9BRE 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=9bre FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9bre OCA], [https://pdbe.org/9bre PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9bre RCSB], [https://www.ebi.ac.uk/pdbsum/9bre PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9bre 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) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.
-Authors: Chen, Y., Tesmer, J.J.G.
+Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors.,Ghosh AK, Chen Y, Gadi RK, Sonawane A, Gamage SP, Tesmer JG Eur J Med Chem. 2025 Jan 15;282:117024. doi: 10.1016/j.ejmech.2024.117024. Epub , 2024 Nov 8. PMID:39549325<ref>PMID:39549325</ref>
-Description: Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL019-21
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Tesmer, J.J.G]]
+<div class="pdbe-citations 9bre" style="background-color:#fffaf0;"></div>
-[[Category: Chen, Y]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Chen Y]]
+[[Category: Tesmer JJG]]