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5he1

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==Human GRK2 in complex with Gbetagamma subunits and CCG224062==
==Human GRK2 in complex with Gbetagamma subunits and CCG224062==
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<StructureSection load='5he1' size='340' side='right' caption='[[5he1]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
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<StructureSection load='5he1' size='340' side='right'caption='[[5he1]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5he1]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HE1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HE1 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5he1]] is a 3 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=5HE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HE1 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZS2:(4~{S})-4-[4-FLUORANYL-3-(ISOQUINOLIN-1-YLMETHYLCARBAMOYL)PHENYL]-~{N}-(1~{H}-INDAZOL-5-YL)-6-METHYL-2-OXIDANYLIDENE-3,4-DIHYDRO-1~{H}-PYRIMIDINE-5-CARBOXAMIDE'>ZS2</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5he0|5he0]], [[5he2|5he2]], [[5he3|5he3]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZS2:(4~{S})-4-[4-FLUORANYL-3-(ISOQUINOLIN-1-YLMETHYLCARBAMOYL)PHENYL]-~{N}-(1~{H}-INDAZOL-5-YL)-6-METHYL-2-OXIDANYLIDENE-3,4-DIHYDRO-1~{H}-PYRIMIDINE-5-CARBOXAMIDE'>ZS2</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5he1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5he1 OCA], [https://pdbe.org/5he1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5he1 RCSB], [https://www.ebi.ac.uk/pdbsum/5he1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5he1 ProSAT]</span></td></tr>
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<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=5he1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5he1 OCA], [http://pdbe.org/5he1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5he1 RCSB], [http://www.ebi.ac.uk/pdbsum/5he1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5he1 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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> [[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, &gt;700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.
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Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.,Waldschmidt HV, Homan KT, Cruz-Rodriguez O, Cato MC, Waninger-Saroni J, Larimore KM, Cannavo A, Song J, Cheung JY, Kirchhoff PD, Koch WJ, Tesmer JJ, Larsen SD J Med Chem. 2016 Apr 28;59(8):3793-807. doi: 10.1021/acs.jmedchem.5b02000. Epub, 2016 Apr 13. PMID:27050625<ref>PMID:27050625</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5he1" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Beta-adrenergic receptor kinase|Beta-adrenergic receptor kinase]]
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*[[Beta adrenergic receptor kinase 3D structures|Beta adrenergic receptor kinase 3D structures]]
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*[[Transducin|Transducin]]
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*[[Transducin 3D structures|Transducin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Cato, M C]]
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[[Category: Homo sapiens]]
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[[Category: Tesmer, J J.G]]
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[[Category: Large Structures]]
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[[Category: Inhibitor complex]]
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[[Category: Cato MC]]
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[[Category: Kinase]]
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[[Category: Tesmer JJG]]
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[[Category: Ph]]
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[[Category: Rg]]
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[[Category: Transferase-transferase inhibitor complex]]
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[[Category: Wd-40]]
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Current revision

Human GRK2 in complex with Gbetagamma subunits and CCG224062

PDB ID 5he1

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