3d9v
From Proteopedia
(New page: '''Unreleased structure''' The entry 3d9v is ON HOLD Authors: Jacobs, M. Description: CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL ''Page seeded by...) |
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| + | {{STRUCTURE_3d9v| PDB=3d9v | SCENE= }} | ||
| - | + | '''CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL''' | |
| - | Description: CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL | ||
| + | ==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. | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 | + | ==About this Structure== |
| + | 3D9V is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=2eto 2eto]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D9V 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:[http://www.ncbi.nlm.nih.gov/pubmed/16249185 16249185] | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
| + | [[Category: Single protein]] | ||
| + | [[Category: Jacobs, M.]] | ||
| + | [[Category: Apoptosis]] | ||
| + | [[Category: Atp-binding]] | ||
| + | [[Category: Coiled coil]] | ||
| + | [[Category: Cytoplasm]] | ||
| + | [[Category: Dimer]] | ||
| + | [[Category: Dimerization]] | ||
| + | [[Category: Fasudil]] | ||
| + | [[Category: Golgi apparatus]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Membrane]] | ||
| + | [[Category: Metal-binding]] | ||
| + | [[Category: Nucleotide-binding]] | ||
| + | [[Category: Phorbol-ester binding]] | ||
| + | [[Category: Phosphoprotein]] | ||
| + | [[Category: Phosphorylation]] | ||
| + | [[Category: Polymorphism]] | ||
| + | [[Category: Serine/threonine-protein kinase]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Zinc]] | ||
| + | [[Category: Zinc-finger]] | ||
| + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:53:01 2008'' | ||
Revision as of 07:53, 11 June 2008
CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL
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
3D9V is a Single protein structure of sequence from Homo sapiens. This structure supersedes the now removed PDB entry 2eto. 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 Wed Jun 11 10:53:01 2008
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Single protein | Jacobs, M. | Apoptosis | Atp-binding | Coiled coil | Cytoplasm | Dimer | Dimerization | Fasudil | Golgi apparatus | Kinase | Membrane | Metal-binding | Nucleotide-binding | Phorbol-ester binding | Phosphoprotein | Phosphorylation | Polymorphism | Serine/threonine-protein kinase | Transferase | Zinc | Zinc-finger
