3qfv | pdb_00003qfv

MRCK beta in complex with TPCA-1

spinqualitylabelsall models 3qfv, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qfv is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, EDO, MG, NM7 Related: 3my4 Gene: CDC42BPB, MRCK beta (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 >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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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