3d9v: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

[[Image:3d9v.jpg|left|200px]]

The ~~entry~~ 3d9v ~~is ON HOLD~~

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~~Authors: Jacobs, M.~~

'''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 09:38:31 2008''

==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''

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+[[Image:3d9v.jpg|left|200px]]
-The entry 3d9v is ON HOLD
+<!--
+The line below this paragraph, containing "STRUCTURE_3d9v", creates the "Structure Box" on the page.
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+or leave the SCENE parameter empty for the default display.
+-->
+{{STRUCTURE_3d9v|  PDB=3d9v  |  SCENE=  }}
-Authors: Jacobs, M.
+'''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 09:38:31 2008''
+==About this Structure==
+D9V 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''