3twj

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<StructureSection load='3twj' size='340' side='right'caption='[[3twj]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='3twj' size='340' side='right'caption='[[3twj]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3twj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TWJ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3twj]] 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=3TWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TWJ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=07R:1-[(3-HYDROXYPHENYL)METHYL]-3-(4-PYRIDIN-4-YL-1,3-THIAZOL-2-YL)UREA'>07R</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.9&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ROCK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=07R:1-[(3-HYDROXYPHENYL)METHYL]-3-(4-PYRIDIN-4-YL-1,3-THIAZOL-2-YL)UREA'>07R</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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=3twj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3twj OCA], [https://pdbe.org/3twj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3twj RCSB], [https://www.ebi.ac.uk/pdbsum/3twj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3twj ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3twj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3twj OCA], [https://pdbe.org/3twj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3twj RCSB], [https://www.ebi.ac.uk/pdbsum/3twj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3twj ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The Rho-associated kinases ROCK1 and ROCK2 are critical for cancer cell migration and invasion, suggesting they may be useful therapeutic targets. In this study, we describe the discovery and development of RKI-1447, a potent small molecule inhibitor of ROCK1 and ROCK2. Crystal structures of the RKI-1447/ROCK1 complex revealed that RKI-1447 is a Type I kinase inhibitor that binds the ATP binding site through interactions with the hinge region and the DFG motif. RKI-1447 suppressed phosphorylation of the ROCK substrates MLC-2 and MYPT-1 in human cancer cells, but had no effect on the phosphorylation levels of the AKT, MEK and S6 kinase at concentrations as high as10 muM. RKI-1447 was also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PAK-meditated lamellipodia and filopodia formation following PDGF and Bradykinin stimulation, respectively. RKI-1447 inhibited migration, invasion and anchorage-independent tumor growth of breast cancer cells. In contrast, RKI-1313, a much weaker analog in vitro, had little effect on the phosphorylation levels of ROCK substrates, migration, invasion or anchorage-independent growth. Lastly RKI-1447 was highly effective at inhibiting the outgrowth of mammary tumors in a transgenic mouse model. In summary, our findings establish RKI-1447 as a potent and selective ROCK inhibitor with significant anti-invasive and anti-tumor activities and offer a preclinical proof-of-concept that justify further examination of RKI-1447 suitability as a potential clinical candidate.
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RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and anti-tumor activities in breast cancer.,Patel RA, Forinash KD, Pireddu R, Sun Y, Sun N, Martin MP, Schonbrunn E, Lawrence NJ, Sebti SM Cancer Res. 2012 Jul 30. PMID:22846914<ref>PMID:22846914</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 3twj" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Rho-associated protein kinase|Rho-associated protein kinase]]
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*[[Rho-associated protein kinase 3D structures|Rho-associated protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Martin MP]]
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[[Category: Martin, M P]]
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[[Category: Schonbrunn E]]
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[[Category: Schonbrunn, E]]
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[[Category: Zhu J-Y]]
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[[Category: Zhu, J Y]]
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[[Category: Dimer]]
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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

Rho-associated protein kinase 1 (ROCK 1) IN COMPLEX WITH RKI1447

PDB ID 3twj

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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