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

@article{Raves1997StructureOA,
  title={Structure of acetylcholinesterase complexed with the nootropic alkaloid, (–)-huperzine A},
  author={Mia L. Raves and Michal Harel and Yuan-Ping Pang and Israel Silman and Alan P. Kozikowski and Joel L. Sussman},
  journal={Nature Structural Biology},
  year={1997},
  volume={4},
  pages={57-63}
}
(–)-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… 

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Characterization of C-10 Substituted Analogues of Huperzine A as Inhibitors of Cholinesterases

TLDR
The observed pharmacological data supports a major role for Y337(F330) in the binding and stereoselectivity of huperzine A for AChE.

Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors.

TLDR
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References

SHOWING 1-10 OF 43 REFERENCES

Mechanism of inhibition of cholinesterases by huperzine A.

Identification of a more potent analogue of the naturally occurring alkaloid huperzine A. Predictive molecular modeling of its interaction with AChE

TLDR
The important finding was made that introduction of an axial methyl group into the C-10 position of huperzine A increased the potency for AChE inhibition 8-fold; the corresponding equatorial isomer was about 1.5-fold less active than huperZine A.

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases

TLDR
Examination of the interaction of the 2 stereoisomers of Huperzine A with cholinesterases and site‐specific mutants that detail the involvement of specific amino acid residues revealed a better fit than (+)‐HuperZine A and implicated Tyr 337(330) in the stereoselectivity ofHuperzines A.

Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase.

TLDR
Results demonstrate that the inhibition of AChE by HUP occurs through association with residues located inside the active site 'gorge,' rather than at the rim of the gorge, and are expected to establish HUP as a lead compound for the design of new anti-AChE drugs.

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

TLDR
Docking studies with the SYSDOC program on acetylcholinesterase (AChE) predict that huperzine A (HA) binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site).

Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.

  • M. HarelI. Schalk J. Sussman
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1993
TLDR
The structural and chemical data show the important role of aromatic groups as binding sites for quaternary ligands in Torpedo acetylcholinesterase, and provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site andtrp-279 to the 'peripheral' anionic site.

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein

TLDR
Modeling of acetylcholine binding to the enzyme suggests that the quaternary ammonium ion is bound not to a negatively charged "anionic" site, but rather to some of the 14 aromatic residues that line the gorge.