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| - | [[Image:2eto.gif|left|200px]]<br /><applet load="2eto" size="350" color="white" frame="true" align="right" spinBox="true" | + | #REDIRECT [[3d9v]] This PDB entry is obsolete and replaced by 3d9v |
| - | caption="2eto, resolution 3.30Å" />
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| - | '''Crystal structure of ROCK I bound to H-1152P a di-methylated variant of fasudil'''<br />
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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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| - | ==About this Structure==
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| - | 2ETO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=H52:'>H52</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ETO OCA].
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| - | ==Reference==
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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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| - | [[Category: Homo sapiens]]
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| - | [[Category: Non-specific serine/threonine protein kinase]]
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| - | [[Category: Single protein]]
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| - | [[Category: Jacobs, M.]]
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| - | [[Category: H52]]
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| - | [[Category: dimer]]
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| - | [[Category: dimerization]]
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| - | [[Category: fasudil]]
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| - | [[Category: kinase]]
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| - | [[Category: phosphorylation]]
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| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:14:27 2008''
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