6ed6

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==Crystal structure of Rock2 with a pyridinylbenzamide based inhibitor==
==Crystal structure of Rock2 with a pyridinylbenzamide based inhibitor==
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<StructureSection load='6ed6' size='340' side='right' caption='[[6ed6]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
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<StructureSection load='6ed6' size='340' side='right'caption='[[6ed6]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6ed6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ED6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ED6 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ed6]] is a 2 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=6ED6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ED6 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=J0P:N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4-(pyridin-4-yl)benzamide'>J0P</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]] 2.86&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6e9w|6e9w]], [[6e99|6e99]], [[6e9l|6e9l]]</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=J0P:N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4-(pyridin-4-yl)benzamide'>J0P</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ROCK2, KIAA0619 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ed6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ed6 OCA], [https://pdbe.org/6ed6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ed6 RCSB], [https://www.ebi.ac.uk/pdbsum/6ed6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ed6 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=6ed6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ed6 OCA], [http://pdbe.org/6ed6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ed6 RCSB], [http://www.ebi.ac.uk/pdbsum/6ed6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ed6 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_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 ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
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[https://www.uniprot.org/uniprot/ROCK2_HUMAN ROCK2_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 ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus.<ref>PMID:10579722</ref> <ref>PMID:15699075</ref> <ref>PMID:16574662</ref> <ref>PMID:17015463</ref> <ref>PMID:19131646</ref> <ref>PMID:19997641</ref> <ref>PMID:21084279</ref> <ref>PMID:21147781</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Co-crystal structures of an early lead compound were obtained in PKA, ROCK1 and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. Aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, were targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Finally, compound 16, a potent and selective pan ROCK inhibitor, was shown to be efficacious in the retinal nerve fiber layer model after oral dosing.
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Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design.,Hobson AD, Judge RA, Aguirre AL, Brown BS, Cui Y, Ding P, Dominguez E, DiGiammarino E, Egan DA, Freiberg GM, Gopalakrishnan SM, Harris CM, Honore MP, Kage KL, Kapecki NJ, Ling C, Ma J, Mack H, Mamo M, Maurus S, McRae B, Moore NS, Mueller BK, Mueller R, Namovic MT, Patel K, Pratt SD, Putman CB, Queeney KL, Sarris KK, Schaffter LM, Stoll VS, Vasudevan A, Wang L, Wang L, Wirthl W, Yach K J Med Chem. 2018 Nov 1. doi: 10.1021/acs.jmedchem.8b01098. PMID:30384606<ref>PMID:30384606</ref>
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==See Also==
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*[[Rho-associated protein kinase 3D structures|Rho-associated protein kinase 3D structures]]
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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 6ed6" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[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: Hobson, A D]]
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[[Category: Hobson AD]]
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[[Category: Judge, R A]]
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[[Category: Judge RA]]
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[[Category: Kinase]]
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[[Category: Rock 2]]
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[[Category: Transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of Rock2 with a pyridinylbenzamide based inhibitor

PDB ID 6ed6

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