5otf: Difference between revisions
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==MRCK beta in complex with BDP-00009066== | ==MRCK beta in complex with BDP-00009066== | ||
<StructureSection load='5otf' size='340' side='right' caption='[[5otf]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='5otf' size='340' side='right'caption='[[5otf]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5otf]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5otf]] is a 1 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=5OTF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OTF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AQ5:(6~{S})-8-(3-pyrimidin-4-yl-1~{H}-pyrrolo[2,3-b]pyridin-4-yl)-1,8-diazaspiro[5.5]undecane'>AQ5</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AQ5:(6~{S})-8-(3-pyrimidin-4-yl-1~{H}-pyrrolo[2,3-b]pyridin-4-yl)-1,8-diazaspiro[5.5]undecane'>AQ5</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=5otf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5otf OCA], [https://pdbe.org/5otf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5otf RCSB], [https://www.ebi.ac.uk/pdbsum/5otf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5otf ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/MRCKB_HUMAN MRCKB_HUMAN] Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A.<ref>PMID:18854160</ref> <ref>PMID:21457715</ref> <ref>PMID:21949762</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5otf" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5otf" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Schuettelkopf | [[Category: Schuettelkopf AW]] | ||
Latest revision as of 04:23, 28 December 2023
MRCK beta in complex with BDP-00009066MRCK beta in complex with BDP-00009066
Structural highlights
FunctionMRCKB_HUMAN Serine/threonine-protein kinase which is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration. Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12C and MYL9/MLC2. In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A.[1] [2] [3] Publication Abstract from PubMedThe myotonic dystrophy-related Cdc42-binding kinases MRCKalpha and MRCKbeta contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKalpha S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKalpha status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKalpha S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy. Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer.,Unbekandt M, Belshaw S, Bower J, Clarke M, Cordes J, Crighton D, Croft DR, Drysdale MJ, Garnett MJ, Gill K, Gray C, Greenhalgh DA, Hall JA, Konczal J, Lilla S, McArthur D, McConnell P, McDonald L, McGarry L, McKinnon H, McMenemy C, Mezna M, Morrice NA, Munro J, Naylor G, Rath N, Schuttelkopf AW, Sime M, Olson MF Cancer Res. 2018 Jan 30. pii: 0008-5472.CAN-17-2870. doi:, 10.1158/0008-5472.CAN-17-2870. PMID:29382705[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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