| Abstract
| - Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the activesite of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayedwith Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes withthe enzyme have been solved by X-ray crystallography. Differences were noted between the IC50 valuesobtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed tosequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of oneof the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279−Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine,which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen inthe crystal structure.
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