| - | ROCK or Rho-associated kinase, a serine/threonine kinase, is an effector, of Rho-dependent signaling and is involved in actin-cytoskeleton assembly, and cell motility and contraction. The ROCK protein consists of several, domains: an N-terminal region, a kinase catalytic domain, a coiled-coil, domain containing a RhoA binding site, and a pleckstrin homology domain., The C-terminal region of ROCK binds to and inhibits the kinase catalytic, domains, and this inhibition is reversed by binding RhoA, a small GTPase., Here we present the structure of the N-terminal region and the kinase, domain. In our structure, two N-terminal regions interact to form a, dimerization domain linking two kinase domains together. This spatial, arrangement presents the kinase active sites and regulatory sequences on a, common face affording the possibility of both kinases simultaneously, interacting with a dimeric inhibitory domain or with a dimeric substrate., The kinase domain adopts a catalytically competent conformation; however, no phosphorylation of active site residues is observed in the structure., We also determined the structures of ROCK bound to four different, ATP-competitive small molecule inhibitors (Y-27632, fasudil, hydroxyfasudil, and H-1152P). Each of these compounds binds with reduced, affinity to cAMP-dependent kinase (PKA), a highly homologous kinase., Subtle differences exist between the ROCK- and PKA-bound conformations of, the inhibitors that suggest that interactions with a single amino acid of, the active site (Ala215 in ROCK and Thr183 in PKA) determine the relative, selectivity of these compounds. Hydroxyfasudil, a metabolite of fasudil, may be selective for ROCK over PKA through a reversed binding orientation.
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| - | The structure of dimeric ROCK I reveals the mechanism for ligand selectivity., Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J, J Biol Chem. 2006 Jan 6;281(1):260-8. Epub 2005 Oct 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16249185 16249185]
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