2aso
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Structure of Rabbit Actin In Complex With Sphinxolide B
OverviewOverview
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.
About this StructureAbout this Structure
2ASO is a Single protein structure of sequence from Oryctolagus cuniculus with CA, ATP and SPX as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity., Allingham JS, Zampella A, D'Auria MV, Rayment I, Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14527-32. Epub 2005 Sep 28. PMID:16192358
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