X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement.
2002
Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (−)-huperzine A, and of its natural homologue (−)-huperzine B. (+)-Huperzine A and (−)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 μM, respectively, compared to 0.18 μM for (−)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (−)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (−)-huperzine A complex. All three interact with the “anionic” subsite of the active site, primarily through π−π stacking and through van der Waals or C−H···π interactions with Trp84 and Phe330. Since their α-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C−H···π interactions, all three maintain similar positions and orientatio...
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