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Structure of acetylcholinesterase complexed with the nootropic alkaloid, (–)-huperzine A

Nature Structural Biology volume 4, pages 57–63 (1997)Cite this article

Abstract

(–)-Huperzine A (HupA) is found in an extract from a club moss that has been used for centuries in Chinese folk medicine. Its action has been attributed to its ability to strongly inhibit acetylcholinesterase (AChE). The crystal structure of the complex of AChE with optically pure HupA at 2.5 Å resolution shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. This structure is compared to the native structure of AChE devoid of any inhibitor as determined to the same resolution. An analysis of the affinities of structural analogues of HupA, correlated with their interactions with the protein, shows the importance of individual hydrophobic interactions between HupA and aromatic residues in the active-site gorge of AChE

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Authors and Affiliations

  1. Department of Structural Biology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Mia L. Raves, Michal Harel & Joel L. Sussman

  2. The Mayo Clinic, Jacksonville, Florida, 32224, USA

    Yuan-Ping Pang

  3. Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Israel Silman

  4. Institute of Cognitive and Computational Sciences, Georgetown University Medical School, Washington, DC, 20007-2197, USA

    Alan P. Kozikowski

  5. Department of Biology, Brookhaven National Laboratory, Upton, New York, 11973-5000, USA

    Joel L. Sussman

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  2. Michal Harel
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  4. Israel Silman
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  5. Alan P. Kozikowski
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  6. Joel L. Sussman
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Raves, M., Harel, M., Pang, YP. et al. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (–)-huperzine A. Nat Struct Mol Biol 4, 57–63 (1997). https://doi.org/10.1038/nsb0197-57

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