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PDBsum entry 2f2u
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References listed in PDB file
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Key reference
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Title
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Molecular mechanism for the regulation of rho-Kinase by dimerization and its inhibition by fasudil.
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Authors
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H.Yamaguchi,
M.Kasa,
M.Amano,
K.Kaibuchi,
T.Hakoshima.
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Ref.
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Structure, 2006,
14,
589-600.
[DOI no: ]
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PubMed id
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Abstract
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Rho-kinase is a key regulator of cytoskeletal events and a promising drug target
in the treatment of vascular diseases and neurological disorders. Unlike other
protein kinases, Rho-kinase requires both N- and C-terminal extension segments
outside the kinase domain for activity, although the details of this requirement
have been elusive. The crystal structure of an active Rho-kinase fragment
containing the kinase domain and both the extensions revealed a head-to-head
homodimer through the N-terminal extension forming a helix bundle that
structurally integrates the C-terminal extension. This structural organization
enables binding of the C-terminal hydrophobic motif to the N-terminal lobe,
which defines the correct disposition of helix alphaC that is important for the
catalytic activity. The bound inhibitor fasudil significantly alters the
conformation and, consequently, the mode of interaction with the catalytic cleft
that contains local structural changes. Thus, both kinase and drug
conformational pliability and stability confer selectivity.
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Figure 2.
Figure 2. Overall Structure of the Kinase Domain of
Rho-Kinase and Comparison with PKA
(A) Ribbon diagram of
Rho-kinase (molecules A). The kinase domain with the C-terminal
extension is shown in cyan (N-terminal lobe), blue (C-terminal
lobe), and red (C-terminal extension containing the hydrophobic
motif). The N-terminal extension forming the CHB domain is
omitted for clarity. All secondary structure elements are
labeled. The bound fasudil is shown as a stick model. Five
catalytically important residues (Lys121, Glu140, Asp214,
Asn219, and Asp232) in addition to the potential phosphorylation
site in the activation loop (Thr249) are shown. The functional
motifs are shown with the same color scheme as in Figure 1A;
magenta, P loop; orange, C loop; yellow, A loop. Dotted
connections between the N-terminal lobe and the C-terminal
extension are for residues omitted in model building due to poor
electron density (see text).
(B) Ribbon diagram of PKA (PDB
code: 1CDK). The bound ATP analog (AMPPNP) is shown as a stick
model. Five catalytically important residues (Lys72, Glu91,
Asp166, Asn171, and Asp184) and the phosphorylated threonine
(pThr197) in the activation loop are shown. The functionally
significant motifs are shown with the same color scheme as in
(A). The PKI peptide is not shown for clarity.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2006,
14,
589-600)
copyright 2006.
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