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PDBsum entry 1qz6
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Structural protein
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PDB id
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1qz6
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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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Trisoxazole macrolide toxins mimic the binding of actin-Capping proteins to actin.
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Authors
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V.A.Klenchin,
J.S.Allingham,
R.King,
J.Tanaka,
G.Marriott,
I.Rayment.
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Ref.
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Nat Struct Biol, 2003,
10,
1058-1063.
[DOI no: ]
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PubMed id
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Abstract
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Marine macrolide toxins of trisoxazole family target actin with high affinity
and specificity and have promising pharmacological properties. We present X-ray
structures of actin in complex with two members of this family, kabiramide C and
jaspisamide A, at a resolution of 1.45 and 1.6 A, respectively. The structures
reveal the absolute stereochemistry of these toxins and demonstrate that their
trisoxazole ring interacts with actin subdomain 1 while the aliphatic side chain
is inserted into the hydrophobic cavity between actin subdomains 1 and 3. The
binding site is essentially the same as the one occupied by the actin-capping
domain of the gelsolin superfamily of proteins. The structural evidence suggests
that actin filament severing and capping by these toxins is also analogous to
that of gelsolin. Consequently, these macrolides may be viewed as small molecule
biomimetics of an entire class of actin-binding proteins.
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Figure 2.
Figure 2. Trisoxazole-containing macrolide toxins bind to the
same site on actin as gelsolin domain 1. (a) The structure of
the actin -jaspisamide A complex in two orientations where actin
is depicted in a ribbon representation and the toxin is shown as
a space-filling model in red. Actin subdomains 1 -4 are labeled.
(b) A space-filling representation of the residues on actin that
interact with kabiramide C (left) and gelsolin domain 1 (right).
The coordinates for gelsolin domain 1 were obtained from the
RCSB (PDB entry 1EQY)5, 6. (c) Overlay of kabiramide C (red,
space-filling representation) and gelsolin domain 1 (blue) based
on the superposition of the actin in their respective complexes.
For gelsolin domain 1 the actin-binding helix, Ser70 -Leu88, is
shown in space-filling representation. (d) Kabiramide C binding
site on actin. Toxin is shown as ball and stick representation
in cyan; labeled amino acid residues contacting kabiramide C are
shown in CPK colors as a space-filling model.
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Figure 3.
Figure 3. Kabiramide C binding to the actin filament may result
in steric clashes with the neighboring actin subunit.
Kabiramide C in G-actin-bound conformation (red) is superimposed
onto the model for F-actin31, 33. For clarity, four actin
subunits are depicted where the filament axis is vertical with
the barbed end at the bottom. The two in the front, shown in
blue and green, reveal the location of kabiramide between
longitudinally contacting actin monomers.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2003,
10,
1058-1063)
copyright 2003.
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