Co-Crystal Structures of Inhibitors with MRCKβ, a Key Regulator of Tumor Cell Invasion

摘要: MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, influence cell shape motility. We report further evidence for contributions invasion cancer cells 3-dimensional matrix assays. In particular, our results indicate combined inhibition together with ROCK significantly greater effects on reducing than blocking either MRCK or alone. To probe kinase ligand pocket, we screened 159 inhibitors an vitro assay found 11 compounds inhibited enzyme activity >80% at 3 µM. Further analysis three hits, Y-27632, Fasudil TPCA-1, revealed low micromolar IC(50) values MRCKβ. also describe crystal structure complex TPCA-1 bound active site kinase. These high-resolution structures reveal highly conserved AGC fold typical dimeric arrangement. The domain is conformation fully-ordered correctly positioned αC helix catalytic residues competent catalysis. Together, these provide validation involvement regulation present valuable starting point future structure-based drug discovery efforts.