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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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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And structure-Activity relationships of pyridine-Based rho kinase (rock) inhibitors.
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Authors
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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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Ref.
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J Med Chem, 2015,
58,
5028-5037.
[DOI no: ]
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PubMed id
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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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Secondary reference #1
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Title
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The structure of dimeric rock i reveals the mechanism for ligand selectivity.
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Authors
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M.Jacobs,
K.Hayakawa,
L.Swenson,
S.Bellon,
M.Fleming,
P.Taslimi,
J.Doran.
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Ref.
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J Biol Chem, 2006,
281,
260-268.
[DOI no: ]
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PubMed id
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Figure 1.
FIGURE 1. Overall structure of the ROCK/Y-27632 complex. A,
the ROCK protein dimer is drawn with  -sheets as arrows and
 -helices as cylinders.
One monomer is drawn in gray, and the others are colored by
protein region. The N-terminal dimerization domain is shown in
red. The N-terminal kinase domain (dark blue) is shown with the
glycine-rich loop drawn in green. The hinge connecting the two
domains is colored orange. The C-terminal kinase domain is shown
in light blue with the activation loop in purple and the kinase
tail in yellow. Y-27632 is shown in the active site near the
glycine-rich loop and the hinge. B, a surface representation of
the dimer is shown where both monomers are colored by region.
Y-27632 is shown in the active site as spheres. A model of the
substrate peptide is shown as a pink cylinder and strand, based
upon a superposition of the ROCK structure and the
PKA/ATP/peptide complex (Protein Data Bank code 1ATP [PDB]
). C and D, an expanded view of the dimerization domain is shown
in two orientations, differing by a 90° rotation. All of the
structure figures were made with PYMOL (58).
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Figure 3.
FIGURE 3. Phosphothreonine-binding site in PKA aligned with
ROCK. The activation loops of PKA (gray) and ROCK (green) are
shown with interactions between side chains and the phosphate
shown as purple dotted lines.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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