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PDBsum entry 2q0r
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Structural protein
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PDB id
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2q0r
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References listed in PDB file
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Key reference
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Title
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A structural basis for regulation of actin polymerization by pectenotoxins.
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Authors
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J.S.Allingham,
C.O.Miles,
I.Rayment.
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Ref.
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J Mol Biol, 2007,
371,
959-970.
[DOI no: ]
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PubMed id
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Abstract
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(PTXs) are polyether macrolides found in certain dinoflagellates, sponges and
shellfish, and have been associated with diarrhetic shellfish poisoning. In
addition to their in vivo toxicity, some PTXs are potently cytotoxic in human
cancer cell lines. Recent studies have demonstrated that disruption of the actin
cytoskeleton may be a key function of these compounds, although no clarification
of their mechanism of action at a molecular level was available. We have
obtained an X-ray crystal structure of PTX-2 bound to actin, which, in
combination with analyses of the effect of PTX-2 on purified actin filament
dynamics, provides a molecular explanation for its effects on actin. PTX-2
formed a 1:1 complex with actin and engaged a novel site between subdomains 1
and 3. Based on models of the actin filament, PTX binding would disrupt key
lateral contacts between the PTX-bound actin monomer and the lower lateral actin
monomer within the filament, thereby capping the barbed-end. The location of
this binding position within the interior of the filament indicates that it may
not be accessible once polymerization has occurred, a hypothesis supported by
our observation that PTX-2 caused filament capping without inducing filament
severing. This mode of action is unique, as other actin filament destabilizing
toxins appear to exclusively disrupt longitudinal monomer contacts, allowing
many of them to sever filaments in addition to capping them. Examination of the
PTX-binding site on actin provides a rationalization for the structure-activity
relationships observed in vivo and in vitro, and may provide a basis for
predicting toxicity of PTX analogues.
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Figure 4.
Figure 4. F-actin severing activity of PTX-2. F-actin (48
μM) in F-buffer was treated with the indicated molar ratio
amounts of PTX-2, latrunculin B (LatB), reidispongiolide A
(RedA), or halichondramide (Hal) for 30 min and then centrifuged
at 20,000g for 30 min. The pellet of each sample following
analysis by SDS-PAGE is shown. The pellets for G-actin (48 μM)
in G-buffer without the addition of toxin are shown as a control
for sedimentation of non-filamentous actin within the tube.
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The above figure is
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2007,
371,
959-970)
copyright 2007.
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