4yve

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==ROCK 1 bound to methoxyphenyl thiazole inhibitor==
==ROCK 1 bound to methoxyphenyl thiazole inhibitor==
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<StructureSection load='4yve' size='340' side='right' caption='[[4yve]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
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<StructureSection load='4yve' size='340' side='right'caption='[[4yve]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4yve]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YVE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YVE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4yve]] 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=4YVE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YVE 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=4KK:2-(3-METHOXYPHENYL)-N-[4-(PYRIDIN-4-YL)-1,3-THIAZOL-2-YL]ACETAMIDE'>4KK</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]] 3.4&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yvc|4yvc]]</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=4KK:2-(3-METHOXYPHENYL)-N-[4-(PYRIDIN-4-YL)-1,3-THIAZOL-2-YL]ACETAMIDE'>4KK</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/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'>[https://proteopedia.org/fgij/fg.htm?mol=4yve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yve OCA], [https://pdbe.org/4yve PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yve RCSB], [https://www.ebi.ac.uk/pdbsum/4yve PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yve 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=4yve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yve OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4yve RCSB], [http://www.ebi.ac.uk/pdbsum/4yve PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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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[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>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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ROCK or Rho-associated kinase, a serine/threonine kinase, is an effector of Rho-dependent signaling and is involved in actin-cytoskeleton assembly and cell motility and contraction. The ROCK protein consists of several domains: an N-terminal region, a kinase catalytic domain, a coiled-coil domain containing a RhoA binding site, and a pleckstrin homology domain. The C-terminal region of ROCK binds to and inhibits the kinase catalytic domains, and this inhibition is reversed by binding RhoA, a small GTPase. Here we present the structure of the N-terminal region and the kinase domain. In our structure, two N-terminal regions interact to form a dimerization domain linking two kinase domains together. This spatial arrangement presents the kinase active sites and regulatory sequences on a common face affording the possibility of both kinases simultaneously interacting with a dimeric inhibitory domain or with a dimeric substrate. The kinase domain adopts a catalytically competent conformation; however, no phosphorylation of active site residues is observed in the structure. We also determined the structures of ROCK bound to four different ATP-competitive small molecule inhibitors (Y-27632, fasudil, hydroxyfasudil, and H-1152P). Each of these compounds binds with reduced affinity to cAMP-dependent kinase (PKA), a highly homologous kinase. Subtle differences exist between the ROCK- and PKA-bound conformations of the inhibitors that suggest that interactions with a single amino acid of the active site (Ala215 in ROCK and Thr183 in PKA) determine the relative selectivity of these compounds. Hydroxyfasudil, a metabolite of fasudil, may be selective for ROCK over PKA through a reversed binding orientation.
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The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.
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The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.,Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J J Biol Chem. 2006 Jan 6;281(1):260-8. Epub 2005 Oct 24. PMID:16249185<ref>PMID:16249185</ref>
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Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.,Green J, Cao J, Bandarage UK, Gao H, Court J, Marhefka C, Jacobs M, Taslimi P, Newsome D, Nakayama T, Shah S, Rodems S J Med Chem. 2015 Jun 12. PMID:26039570<ref>PMID:26039570</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
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<div class="pdbe-citations 4yve" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Rho-associated protein kinase|Rho-associated protein kinase]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Homo sapiens]]
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[[Category: Jacobs, M D]]
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[[Category: Large Structures]]
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[[Category: Dimer]]
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[[Category: Jacobs MD]]
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[[Category: Dimerization]]
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[[Category: Kinase]]
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[[Category: Myosin]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

ROCK 1 bound to methoxyphenyl thiazole inhibitor

PDB ID 4yve

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