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

Nature Structural Biologyvolume 4pages5763 (1997) | Download Citation



(–)-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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Author information


  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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