3ncz

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==X-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with a potent 2H-isoquinolin-1-one inhibitor==
==X-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with a potent 2H-isoquinolin-1-one inhibitor==
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<StructureSection load='3ncz' size='340' side='right' caption='[[3ncz]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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<StructureSection load='3ncz' size='340' side='right'caption='[[3ncz]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3ncz]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NCZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NCZ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3ncz]] is a 4 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=3NCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NCZ 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=3NC:CIS-4-AMINO-N-(7-CHLORO-1-OXO-1,2-DIHYDROISOQUINOLIN-6-YL)CYCLOHEXANECARBOXAMIDE'>3NC</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&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ndm|3ndm]]</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=3NC:CIS-4-AMINO-N-(7-CHLORO-1-OXO-1,2-DIHYDROISOQUINOLIN-6-YL)CYCLOHEXANECARBOXAMIDE'>3NC</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ROCK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3ncz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ncz OCA], [https://pdbe.org/3ncz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ncz RCSB], [https://www.ebi.ac.uk/pdbsum/3ncz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ncz ProSAT]</span></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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=3ncz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ncz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ncz RCSB], [http://www.ebi.ac.uk/pdbsum/3ncz PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/ROCK1_HUMAN ROCK1_HUMAN] Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, PFN1 and PPP1R12A. Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress. Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis. Plays a role in terminal erythroid differentiation. May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles. Promotes keratinocyte terminal differentiation.<ref>PMID:8617235</ref> <ref>PMID:9722579</ref> <ref>PMID:10436159</ref> <ref>PMID:10652353</ref> <ref>PMID:11018042</ref> <ref>PMID:11283607</ref> <ref>PMID:17158456</ref> <ref>PMID:18694941</ref> <ref>PMID:18573880</ref> <ref>PMID:19036714</ref> <ref>PMID:19181962</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21072057</ref>
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Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 which demonstrates sustained blood pressure normalization in an SHR blood pressure reduction model was identified through this effort.
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Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats.,Ginn JD, Bosanac T, Chen R, Cywin C, Hickey E, Kashem M, Kerr S, Kugler S, Li X, Prokopowicz A 3rd, Schlyer S, Smith JD, Turner MR, Wu F, Young ER Bioorg Med Chem Lett. 2010 Sep 1;20(17):5153-6. Epub 2010 Aug 1. PMID:20678931<ref>PMID:20678931</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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==See Also==
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</div>
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*[[Rho-associated protein kinase 3D structures|Rho-associated protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Li, X]]
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[[Category: Li X]]
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[[Category: Dimer]]
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[[Category: Phosphorylation]]
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[[Category: Rho kinase]]
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[[Category: Transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

X-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with a potent 2H-isoquinolin-1-one inhibitor

PDB ID 3ncz

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