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PDBsum entry 1q8w
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Transferase/transferase inhibitor
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PDB id
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1q8w
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Protein kinase a in complex with rho-Kinase inhibitors y-27632, Fasudil, And h-1152p: structural basis of selectivity.
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Authors
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C.Breitenlechner,
M.Gassel,
H.Hidaka,
V.Kinzel,
R.Huber,
R.A.Engh,
D.Bossemeyer.
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Ref.
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Structure, 2003,
11,
1595-1607.
[DOI no: ]
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PubMed id
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Abstract
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Protein kinases require strict inactivation to prevent spurious cellular
signaling; overactivity can cause cancer or other diseases and necessitates
selective inhibition for therapy. Rho-kinase is involved in such processes as
tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal
adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase
inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral
vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity
and potency. We have determined the crystal structures of HA-1077, H-1152P, and
Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to
analyze Rho-kinase inhibitor binding properties. Features conserved between PKA
and Rho-kinase are involved in the key binding interactions, while a combination
of residues at the ATP binding pocket that are unique to Rho-kinase may explain
the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site
potentially points toward PKA regulatory domain interaction modulators.
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Figure 6.
Figure 6. Comparison of HA-1077 and H-1152POverlay of
HA-1077 and H-1152P demonstrates the colocalization of the
isoquinoline atoms with respect to the surrounding residues.
Both inhibitor molecules form an H bond to the backbone amide of
Val123 in the hinge region. The position of the homopiperazine
rings, however, diverge by ca. 1.5 Å. Consequently, H bonds
between the homopiperazine nitrogen and Glu127 and Glu170 are
formed only in the PKA-1077 complex. The contact between C10 and
Thr183, which prevents as a steric clash a HA-1077-like
positioning of the H-1152P homopiperazine ring, is shown as a
red double arrow.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2003,
11,
1595-1607)
copyright 2003.
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