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PKA as a Model for Rho Kinase: Structures of PKA

with Rho Kinase Inhibitors Y-27632, Fasudil (HA-1077) and H-1152P

As a serine-threonine kinase of the AGC group, Rho kinase possesses a catalytic domain closely related to other AGC group kinases, among them PKA, PKB, PKC and PKG; although no crystal structure of Rho kinase has been reported yet. The close relationship between PKA and Rho kinase (37% identical) and the well-established crystallization conditions for PKA make PKA a suitable model system for studying Rho kinase inhibitors. Furthermore, cocrystallization of PKA with Rho kinase inhibitors helps identify factors governing cross selectivity of protein kinase inhibitors. The importance of sidechain differences in the ATP binding pocket for inhibitor selectivity has been shown previously with Erk2 (Fox et al. 1998).

To avoid confusion, we will use the term 'Rho kinase' for the two enzymes of this family: Rho-associated, coiled-coil-containing protein kinase p160R0CK (gene: ROCK1) and Rho kinase (gene: ROCK2). They are highly homologous in the kinase domain (96%), especially in ATP pocket and are identical in all residues in contact with the inhibitors.

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