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2etk

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{{STRUCTURE_2etk| PDB=2etk | SCENE= }}
{{STRUCTURE_2etk| PDB=2etk | SCENE= }}
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'''Crystal Structure of ROCK 1 bound to hydroxyfasudil'''
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===Crystal Structure of ROCK 1 bound to hydroxyfasudil===
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==Overview==
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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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(as it appears on PubMed at http://www.pubmed.gov), where 16249185 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16249185}}
==About this Structure==
==About this Structure==
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[[Category: Hydroxyfasudil]]
[[Category: Hydroxyfasudil]]
[[Category: Kinase]]
[[Category: Kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:15:21 2008''

Revision as of 12:15, 28 July 2008

Image:2etk.png

Template:STRUCTURE 2etk

Crystal Structure of ROCK 1 bound to hydroxyfasudil

Template:ABSTRACT PUBMED 16249185

About this Structure

2ETK 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

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