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PDBsum entry 4yvc
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Transferase/transferase inhibitor
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PDB id
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4yvc
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Rock 1 bound to thiazole inhibitor
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Structure:
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Rho-associated protein kinase 1. Chain: a, b. Fragment: n-terminal kinase domain (unp residues 6-415). Synonym: renal carcinoma antigen ny-ren-35, rho-associated, coiled- coil-containing protein kinase 1, coiled-coil-containing protein kinase i, rock-i, p160 rock-1, p160rock. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: rock1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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3.20Å
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R-factor:
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0.193
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R-free:
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0.221
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Authors:
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M.D.Jacobs
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Key ref:
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J.Green
et al.
(2015).
Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.
J Med Chem,
58,
5028-5037.
PubMed id:
DOI:
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Date:
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19-Mar-15
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Release date:
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10-Jun-15
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PROCHECK
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Headers
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References
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Q13464
(ROCK1_HUMAN) -
Rho-associated protein kinase 1 from Homo sapiens
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Seq:
Struc:
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1354 a.a.
388 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
58:5028-5037
(2015)
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PubMed id:
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Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.
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J.Green,
J.Cao,
U.K.Bandarage,
H.Gao,
J.Court,
C.Marhefka,
M.Jacobs,
P.Taslimi,
D.Newsome,
T.Nakayama,
S.Shah,
S.Rodems.
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ABSTRACT
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The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases
that act on substrates associated with cellular motility, morphology, and
contraction and are of therapeutic interest in diseases associated with cellular
migration and contraction, such as hypertension, glaucoma, and erectile
dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through
high-throughput screening, systematic exploration of SAR, and application of
structure-based design, led to potent and selective ROCK inhibitors. Compound 37
represents significant improvements in inhibition potency, kinase selectivity,
and CYP inhibition and possesses pharmacokinetics suitable for in vivo
experimentation.
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Links
