2etr
From Proteopedia
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'''Crystal Structure of ROCK I bound to Y-27632''' | '''Crystal Structure of ROCK I bound to Y-27632''' | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Jacobs, M.]] | [[Category: Jacobs, M.]] | ||
| - | [[Category: | + | [[Category: Dimer]] |
| - | [[Category: | + | [[Category: Dimerization]] |
| - | [[Category: | + | [[Category: Kinase]] |
| - | [[Category: | + | [[Category: Phosphorylation]] |
| - | [[Category: | + | [[Category: Yoshitomi]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:06:23 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 00:06, 4 May 2008
Crystal Structure of ROCK I bound to Y-27632
Overview
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.
About this Structure
2ETR is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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:16249185 Page seeded by OCA on Sun May 4 03:06:23 2008
