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Crystal structures of monomeric actin bound to cytochalasin D.

Nair UB, Joel PB, Wan Q, Lowey S, Rould MA, Trybus KM
J Mol Biol 384 848-64 (2008)
Related entries: 3eks, 3el2

Cited: 45 times
EuropePMC logo PMID: 18938176

Abstract

The fungal toxin cytochalasin D (CD) interferes with the normal dynamics of the actin cytoskeleton by binding to the barbed end of actin filaments. Despite its widespread use as a tool for studying actin-mediated processes, the exact location and nature of its binding to actin have not been previously determined. Here we describe two crystal structures of an expressed monomeric actin in complex with CD: one obtained by soaking preformed actin crystals with CD, and the other obtained by cocrystallization. The binding site for CD, in the hydrophobic cleft between actin subdomains 1 and 3, is the same in the two structures. Polar and hydrophobic contacts play equally important roles in CD binding, and six hydrogen bonds stabilize the actin-CD complex. Many unrelated actin-binding proteins and marine toxins target this cleft and the hydrophobic pocket at the front end of the cleft (viewing actin with subdomain 2 in the upper right corner). CD differs in that it binds to the back half of the cleft. The ability of CD to induce actin dimer formation and actin-catalyzed ATP hydrolysis may be related to its unique binding site and the necessity to fit its bulky macrocycle into this cleft. Contacts with residues lining this cleft appear to be crucial to capping and/or severing. The cocrystallized actin-CD structure also revealed changes in actin conformation. An approximately 6 degrees rotation of the smaller actin domain (subdomains 1 and 2) with respect to the larger domain (subdomains 3 and 4) results in small changes in crystal packing that allow the D-loop to adopt an extended loop structure instead of being disordered, as it is in most crystal structures of actin. We speculate that these changes represent a potential conformation that the actin monomer can adopt on the pathway to polymerization or in the filament.

Articles - 3eku mentioned but not cited (4)

  1. Crystal structures of monomeric actin bound to cytochalasin D. Nair UB, Joel PB, Wan Q, Lowey S, Rould MA, Trybus KM. J Mol Biol 384 848-864 (2008)
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  4. Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics. Dans MG, Piirainen H, Nguyen W, Khurana S, Mehra S, Razook Z, Geoghegan ND, Dawson AT, Das S, Parkyn Schneider M, Jonsdottir TK, Gabriela M, Gancheva MR, Tonkin CJ, Mollard V, Goodman CD, McFadden GI, Wilson DW, Rogers KL, Barry AE, Crabb BS, de Koning-Ward TF, Sleebs BE, Kursula I, Gilson PR. PLoS Biol 21 e3002066 (2023)


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  1. Control of actin filament treadmilling in cell motility. Bugyi B, Carlier MF. Annu Rev Biophys 39 449-470 (2010)
  2. The chemistry and biology of cytochalasans. Scherlach K, Boettger D, Remme N, Hertweck C. Nat Prod Rep 27 869-886 (2010)
  3. Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton. Gao J, Nakamura F. Int J Mol Sci 23 2118 (2022)
  4. Actin-Interacting Amphidinolides: Syntheses and Mechanisms of Action of Amphidinolides X, J, and K. Costa AM. Molecules 28 5249 (2023)
  5. Cytochalasans and Their Impact on Actin Filament Remodeling. Lambert C, Schmidt K, Karger M, Stadler M, Stradal TEB, Rottner K. Biomolecules 13 1247 (2023)

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Related citations provided by authors (1)

  1. Crystal Structures of Expressed Non-polymerizable Monomeric Actin in the ADP and ATP states. Rould MA, Wan Q, Joel PB, Lowey S, Trybus KM J. Biol. Chem. 281 31909-31919 (2006)

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