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PDBsum entry 2asm
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Structural protein
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PDB id
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2asm
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References listed in PDB file
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Key reference
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Title
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Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity.
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Authors
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J.S.Allingham,
A.Zampella,
M.V.D'Auria,
I.Rayment.
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Ref.
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Proc Natl Acad Sci U S A, 2005,
102,
14527-14532.
[DOI no: ]
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PubMed id
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Abstract
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Marine macrolides that disrupt the actin cytoskeleton are promising candidates
for cancer treatment. Here, we present the actin-bound x-ray crystal structures
of reidispongiolide A and C and sphinxolide B, three marine macrolides found
among a recently discovered family of cytotoxic compounds. Their structures
allow unequivocal assignment of the absolute configuration for each compound. A
comparison of their actin-binding site to macrolides found in the trisoxazole
family, as well as the divalent macrolide, swinholide A, reveals the existence
of a common binding surface for a defined segment of their macrocyclic ring.
This surface is located on a hydrophobic patch adjacent to the cleft separating
domains 1 and 3 at the barbed-end of actin. The large area surrounding this
surface accommodates a wide variety of conformations and designs observed in the
macrocyclic component of barbed-end-targeting macrolides. Conversely, the
binding pocket for the macrolide tail, located within the cleft itself, shows
very limited variation. Functional characterization of these macrolides by using
in vitro actin filament severing and polymerization assays demonstrate the
necessity of the N-methyl-vinylformamide moiety at the terminus of the macrolide
tail for toxin potency. These analyses also show the importance of stable
interactions between the macrocyclic ring and the hydrophobic patch on actin for
modifying filament structure and how this stability can be compromised by subtle
changes in macrolactone ring composition. By identifying the essential
components of these complex natural products that underlie their high actin
affinity, we have established a framework for designing new therapeutic agents.
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Figure 3.
Fig. 3. Overlay of RedA, SphB, and KabC on actin. (A) RedA
(green sticks) and SphB (cyan sticks) are shown superimposed in
their actin-bound conformation on a surface drawing of actin.
Common actin residue contacts are shown in salmon. Residues
contacting RedA but not SphB are shown in yellow. Selected atoms
and the lactone ring of each toxin have been labeled for
reference. (B) RedA (green sticks) and KabC (yellow sticks) are
shown superimposed in their actin-bound conformation. Residues
that are common to the binding of both RedA and KabC are colored
salmon. KabC atom numbers are given primes ('). The coordinates
for KabC actin were obtained from Protein Data Bank entry 1QZ5
[PDB]
. Toxins were superimposed on actin by using the program
SUPERPOSE in CCP4.
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Figure 4.
Fig. 4. RedA and KabC contacts on actin. (A) Stereoview of
the tail portions of RedA (green ball and stick) and KabC
(yellow ball and stick) bound to actin. RedA actin is shown in
orange. KabC actin is shown in blue. Contact residues are shown
as sticks. The N-methyl-vinylformamide moieties of RedA and KabC
are depicted with bridging water molecules from each complex.
Waters from the RedA-actin complex are pink; waters from the
KabC-actin complex are violet. (B) Stereoview of the ring
portions of RedA and KabC. Coloring is as described in A.
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