3D9V

CRYSTAL STRUCTURE OF ROCK I BOUND TO H-1152P A DI-METHYLATED VARIANT OF FASUDIL

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3D9V の概要

• エントリーDOI: 10.2210/pdb3d9v/pdb
• 分子名称: Rho-associated protein kinase 1, (S)-2-METHYL-1-[(4-METHYL-5-ISOQUINOLINE)SULFONYL]-HOMOPIPERAZINE (2 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q13464
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96663.41

構造登録者

Jacobs, M. (登録日: 2008-05-27, 公開日: 2008-06-10, 最終更新日: 2024-02-21)

主引用文献

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

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: 16249185
DOI: 10.1074/jbc.M508847200

実験手法

X-RAY DIFFRACTION (3.3 Å)