2ASM

Structure of Rabbit Actin In Complex With Reidispongiolide A

Summary for 2ASM

• Entry DOI: 10.2210/pdb2asm/pdb
• Related: 1qz5 1qz6 1s22 2ASO 2ASP
• Descriptor: Actin, alpha skeletal muscle, CALCIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: actin, reidispongiolide a, marine macrolide, toxin, filament capping, filament severing, structural protein
• Biological source: Oryctolagus cuniculus (rabbit)
• Cellular location: Cytoplasm, cytoskeleton: P68135
• Total number of polymer chains: 1
• Total formula weight: 43718.56

Authors

Allingham, J.S.,Zampella, A.,D'Auria, M.V.,Rayment, I. (deposition date: 2005-08-23, release date: 2005-10-11, Last modification date: 2023-10-25)

Primary citation

Allingham, J.S.,Zampella, A.,D'Auria, M.V.,Rayment, I.
Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity
Proc.Natl.Acad.Sci.Usa, 102:14527-14532, 2005

PubMed Abstract: 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.

PubMed: 16192358
DOI: 10.1073/pnas.0502089102

Experimental method

X-RAY DIFFRACTION (1.6 Å)