5ukm
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==bovine GRK2 in complex with human Gbetagamma subunits and CCG258208 (14as)== | |
| + | <StructureSection load='5ukm' size='340' side='right' caption='[[5ukm]], [[Resolution|resolution]] 3.03Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5ukm]] is a 3 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UKM FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ukm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ukm OCA], [http://pdbe.org/5ukm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ukm RCSB], [http://www.ebi.ac.uk/pdbsum/5ukm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ukm ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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). [[http://www.uniprot.org/uniprot/GBG2_HUMAN GBG2_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [[http://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5ukm" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Cruz-Rodriguez, O]] | ||
| + | [[Category: Tesmer, J J.G]] | ||
| + | [[Category: Inhibitor complex]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Transferase-signaling protein complex]] | ||
Revision as of 11:36, 12 April 2017
bovine GRK2 in complex with human Gbetagamma subunits and CCG258208 (14as)
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