Dawn Wong - X-ray structures of TcAChE complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active-site rearrangement

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      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.

      PMID: 12196020





      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+