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A single amino acid residue can determine the sensitivity of SERCAs to artemisinins

Nature Structural & Molecular Biology volume 12, pages 628–629 (2005)Cite this article

A Corrigendum to this article was published on 01 February 2012

Abstract

Artemisinins are the most important class of antimalarial drugs. They specifically inhibit PfATP6, a SERCA-type ATPase of Plasmodium falciparum. Here we show that a single amino acid in transmembrane segment 3 of SERCAs can determine susceptibility to artemisinin. An L263E replacement of a malarial by a mammalian residue abolishes inhibition by artemisinins. Introducing residues found in other Plasmodium spp. also modulates artemisinin sensitivity, suggesting that artemisinins interact with the thapsigargin-binding cleft of susceptible SERCAs.

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Figure 1: Inhibitor-binding sites.

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Acknowledgements

This study was supported by the Wellcome Trust (grant 074395). We thank D. Fidock for invaluable discussions.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Infectious Diseases, St. George's Hospital Medical School, London, SW17 0RE, UK

    Anne-Catrin Uhlemann, Ursula Eckstein-Ludwig & Sanjeev Krishna

  2. Department of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Angus Cameron & Leo Brady

  3. Departments of Physiology and Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, 10032, New York, USA

    Jorge Fischbarg, Pavel Iserovich & Felipe A Zuniga

  4. Department of Biochemistry and Molecular Biology, University of Southampton, Southampton, SO16 7PX, UK

    Malcolm East & Anthony Lee

  5. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China

    Richard K Haynes

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  1. Anne-Catrin Uhlemann
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Correspondence to Sanjeev Krishna.

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Uhlemann, AC., Cameron, A., Eckstein-Ludwig, U. et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol 12, 628–629 (2005). https://doi.org/10.1038/nsmb947

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