View source for 3qfv


==MRCK beta in complex with TPCA-1==
<StructureSection load='3qfv' size='340' side='right'caption='[[3qfv]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3qfv]] 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=3QFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QFV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NM7:2-(CARBAMOYLAMINO)-5-(4-FLUOROPHENYL)THIOPHENE-3-CARBOXAMIDE'>NM7</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=3qfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qfv OCA], [https://pdbe.org/3qfv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qfv RCSB], [https://www.ebi.ac.uk/pdbsum/3qfv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qfv ProSAT]</span></td></tr>
</table>
== 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;">
== Publication Abstract from PubMed ==
MRCKalpha and MRCKbeta (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKalpha and MRCKbeta influence cell shape and motility. We report further evidence for MRCKalpha and MRCKbeta contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKalpha and MRCKbeta together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKbeta kinase assay and found 11 compounds that inhibited enzyme activity &gt;80% at 3 microM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC(50) values for MRCKalpha and MRCKbeta. We also describe the crystal structure of MRCKbeta in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned alphaC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts.

Co-crystal structures of inhibitors with MRCKbeta, a key regulator of tumor cell invasion.,Heikkila T, Wheatley E, Crighton D, Schroder E, Boakes A, Kaye SJ, Mezna M, Pang L, Rushbrooke M, Turnbull A, Olson MF PLoS One. 2011;6(9):e24825. Epub 2011 Sep 20. PMID:21949762<ref>PMID:21949762</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3qfv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Boakes A]]
[[Category: Crighton D]]
[[Category: Heikkila TJ]]
[[Category: Kaye SJ]]
[[Category: Mezna M]]
[[Category: Olson MF]]
[[Category: Pang L]]
[[Category: Rushbrooke M]]
[[Category: Schroder E]]
[[Category: Turnbull A]]
[[Category: Wheatley E]]