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Latrunculin alters the actin-monomer subunit interface to prevent polymerization

Nature Cell Biology volume 2, pages 376–378 (2000)Cite this article

Latrunculin-A is a drug that is capable of rapidly, reversibly and specifically disrupting the actin cytoskeleton1. The efficacy of its action has made it a compound of choice in many cell-biology laboratories, supplanting the classic actin-depolymerizing drug cytochalasin-D. One reason for this is that the mode of action of latrunculin seems to be less complex than that of cytochalasin. Whereas the latter affects the kinetics of actin-filament polymerization at both the barbed and pointed ends, latrunculin-A seems to associate only with actin monomers, thereby preventing them from repolymerizing into filaments2. The association of latrunculin with monomeric, rather than filamentous, actin gave us the opportunity to further our understanding of this interaction by detailed structural analysis of actin monomers using crystallographic techniques. Here we show the first high-resolution structure of an actin-disrupting drug in association with actin and discuss how its interactions with actin, and the conformational changes that its binding causes, may explain its mode of action within the cell.

Specific contacts (such as hydrogen bonds) are formed at the Y69 site in subdomain II, at the T186 and R210 sites in subdomain IV and at the D157 site in subdomain III (Fig. 2b). The 2-thiazolidinone group, which is rare in biology, fits neatly into a pocket and every polar latrunculin atom, except the O2-ester oxygen, forms a hydrogen bond with actin. These findings indicate that latrunculin may act to prevent dissociation of the nucleotide buried in the cleft by bridging subdomains II and IV.

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Figure 1: Latrunculin and actin structures.
Figure 2: Crystal structure of the latrunculin–actin complex.

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Acknowledgements

We are grateful for use of facilities at SRS, Daresbury, UK and at EMBL Hamburg (European Union HCMP LIP). This work was funded by the Wellcome Trust grant 040280 (to P.M.) and by Wellcome Career Development Award 050934 /Z/ 97 (to K.R.A.).

Correspondence and requests for materials should be addressed to P.M. Coordinates have been deposited in the protein data bank under accession numbers 1ESV for actin–gelsolin complex with latrunculin and 1EQY for the complex without toxin.

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Authors and Affiliations

  1. The Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, Swann Building, King’s Buildings, Mayfield Road, Edinburgh, EH9 3JR, UK

    Walter M. Morton & Paul J. McLaughlin

  2. Institute of Biomedical and Life Sciences, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, UK

    Kathryn R. Ayscough

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  1. Walter M. Morton
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Correspondence to Paul J. McLaughlin.

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Morton, W., Ayscough, K. & McLaughlin, P. Latrunculin alters the actin-monomer subunit interface to prevent polymerization. Nat Cell Biol 2, 376–378 (2000). https://doi.org/10.1038/35014075

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