Publication Details (including relevant citation information):
Dvir, H.; Jiang, H. L.; Wong, D. M.; Harel, M.; Chetrit, M.; He, X. C.; Tang, X. C.; Silman, I.; Bai, D. L.; Sussman, J. L.
X-ray structures of TcAChE complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active-site rearrangement.
Biochemistry 2002, 41, 10810-10818.
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 microM, respectively, compared to 0.18 microM 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 Å 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 p-p stacking and through van der Walls or C-H...p interactions with Trp84 and Phe330. Since their a-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H...p interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the 'oxyanion' hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged 'oxyanion hole' characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charge or neutral.
Address (URL): http://dx.doi.org/10.1021/bi020151+