3qfv

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 Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.65Å Ligands: CL, EDO, MG, NM7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. 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

Proteopedia Page Contributors and Editors (what is this?)

OCA