STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH THE NOOTROPIC ALKALOID, (-)-HUPERZINE-A

(-)-Huperzine A (HupA) is found in an extract from a club moss that ha s been used for centuries in Chinese folk medicine. Its action has bee n attributed to its ability to strongly inhibit acetylcholinesterase ( AChE), The crystal structure of the complex of AChE with optically pur e HupA at 2.5 Angstrom resolution shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with pr otein residues to explain its high affinity, This structure is compare d to the native structure of AChE devoid of any inhibitor as determine d 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