Summary for 3D9V
| Entry DOI | 10.2210/pdb3d9v/pdb |
| Descriptor | Rho-associated protein kinase 1, (S)-2-METHYL-1-[(4-METHYL-5-ISOQUINOLINE)SULFONYL]-HOMOPIPERAZINE (2 entities in total) |
| Functional Keywords | dimer, dimerization, kinase, phosphorylation, fasudil, apoptosis, atp-binding, coiled coil, cytoplasm, golgi apparatus, membrane, metal-binding, nucleotide-binding, phorbol-ester binding, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase, zinc, zinc-finger |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm: Q13464 |
| Total number of polymer chains | 2 |
| Total formula weight | 96663.41 |
| Authors | Jacobs, M. (deposition date: 2008-05-27, release date: 2008-06-10, Last modification date: 2024-02-21) |
| Primary citation | Jacobs, M.,Hayakawa, K.,Swenson, L.,Bellon, S.,Fleming, M.,Taslimi, P.,Doran, J. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J.Biol.Chem., 281:260-268, 2006 Cited by PubMed Abstract: 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. PubMed: 16249185DOI: 10.1074/jbc.M508847200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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