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Drug-Target Interaction

Drug

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PubChem ID:163751
Structure:
Synonyms:
105628-07-7
133337-43-6
1H-1,4-Diazepine, hexahydro-1-(5-isoquinolinylsulfonyl)-,
1H-1,4-Diazepine, hexahydro-1-(5-isoquinolinylsulfonyl)-, monohydrochloride
AT 877 hydrochloride
AT-877
C14H17N3O2S.HCl
D01840
Eril
Fasdil
fasudil
Fasudil hydrochloride
Fasudil hydrochloride (JAN)
HA 1077 hydrochloride
HA-1077
HA-1077 DIHYDROCHLORIDE
Hexahydro-1-(5-isoquinolinylsulfonyl)-1H-1,4-diazepine monohydrochloride
LS-60222
MLS000069344
NCGC00180915-01
SMR000058993
ATC-Codes:

Target

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Uniprot ID:KAPCG_HUMAN
Synonyms:
cAMP-dependent protein kinase catalytic subunit gamma
PKA C-gamma
EC-Numbers:2.7.11.11
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

16249185
The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.. Marc Jacobs; Koto Hayakawa; Lora Swenson; Steven Bellon; Mark Fleming; Paul Taslimi; John Doran (2006) The Journal of biological chemistry display 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.