Nature Structural Biology
4, 57 - 63 (1997)
doi:10.1038/nsb0197-57
Structure of acetylcholinesterase complexed with the nootropic alkaloid, (−)-huperzine AMia L. Raves1, Michal Harel1, Yuan-Ping Pang2, Israel Silman3, Alan P. Kozikowski4
& Joel L. Sussman1, 5, 6
1Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel
2The Mayo Clinic, Jacksonville, Florida 32224, USA
3Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel
4Institute of Cognitive and Computational Sciences, Georgetown University Medical School, Washington, DC 20007-2197, USA
5Department of Biology, Brookhaven National Laboratory, Upton, New York 11973-5000, USA
6joel@sgjs3.weizmann.ac.il (−)-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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