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PDBsum entry 1mux
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Calcium-binding
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PDB id
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1mux
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References listed in PDB file
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Key reference
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Title
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Solution structure of calmodulin-W-7 complex: the basis of diversity in molecular recognition.
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Authors
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M.Osawa,
M.B.Swindells,
J.Tanikawa,
T.Tanaka,
T.Mase,
T.Furuya,
M.Ikura.
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Ref.
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J Mol Biol, 1998,
276,
165-176.
[DOI no: ]
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PubMed id
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Abstract
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The solution structure of calcium-bound calmodulin (CaM) complexed with an
antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), has been
determined by multidimensional NMR spectroscopy. The structure consists of one
molecule of W-7 binding to each of the two domains of CaM. In each domain, the
W-7 chloronaphthalene ring interacts with four methionine methyl groups and
other aliphatic or aromatic side-chains in a deep hydrophobic pocket, the site
responsible for CaM binding to CaM-dependent enzymes such as myosin light chain
kinases (MLCKs) and CaM kinase II. This competitive binding at the same site
between W-7 and CaM-dependent enzymes suggests the mechanism by which W-7
inhibits CaM to activate the enzymes. The orientation of the W-7 naphthalene
ring in the N-terminal pocket is rotated approximately 40 degrees with respect
to that in the C-terminal pocket. The W-7 ring orientation differs significantly
from the Trp800 indole ring of smooth muscle MLCK bound to the C-terminal pocket
and the phenothiazine ring of trifluoperazine bound to the N or C-terminal
pocket. These comparative structural analyses demonstrate that the two
hydrophobic pockets of CaM can accommodate a variety of bulky aromatic rings,
which provides a plausible structural basis for the diversity in CaM-mediated
molecular recognition.
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Figure 5.
Figure 5. Fifty per cent inhibitory concentrations (IC50)
for Ca
2+
-CaM dependent activation of phosphodiester-
ase by W-7 derivatives containing a different substituent
atom at position 5: W-7(H), W-7(F), W-7, W-7(Br), and
W-7(I) (Tanaka et al., 1982; MacNeil et al., 1988). IC50 is
plotted against van der Waals radius and electronegativ-
ity (inset) for halogen atoms and hydrogen.
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Figure 8.
Figure 8. a,
1
H chemical shift
changes for Ca
2+
-CaM methyl
groups binding to W-7. b, W-7
binding site in the N-terminal
domain; and c, W-7 binding site in
the C-terminal domain of Ca
2+
-CaM
complexed with W-7 and Ca
2+
-CaM
(Chattopadhyaya et al., 1992). The
C
a
carbon atoms are superimposed.
Hydrophobic side-chains of Ca
2+
-
CaM/W-7 complex within 5 Å of
W-7 are shown in magenta, and
corresponding side-chains of Ca
2+
-
CaM are shown as blue sticks. W-7
is shown as a space-filling model
with chlorine in orange, sulfur in
yellow, oxygen in red, nitrogen in
blue, carbon in green, and hydrogen
in white.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1998,
276,
165-176)
copyright 1998.
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