3-DIMENSIONAL STRUCTURE OF A COMPLEX OF E2020 WITH ACETYLCHOLINESTERASE FROM TORPEDO-CALIFORNICA

The 3D structure of a complex of the anti-Alzheimer drug, E2020, also known as Aricept(R), with Torpedo californica acetylcholinesterase is reported. The X-ray structure, at 2.5 Angstrom resolution, shows that the elongated E2020 molecule spans the entire length of the active-sit e gorge of the enzyme. It thus interacts with both the 'anionic' subsi te, at the bottom of the gorge, and with the peripheral anionic site, near its entrance, via aromatic stacking interactions with conserved a romatic residues. It does not interact directly with either the cataly tic triad or with the 'oxyanion hole'. Although E2020 is a chiral mole cule, and both the S and R enantiomers have similar affinity for the e nzyme, only the R enantiomer is bound within the active-site gorge whe n the racemate is soaked into the crystal. The selectivity of E2020 fo r acetylcholinesterase, relative to butyrylcholinesterase, can be ascr ibed primarily to its interactions with Trp279 and Phe330, which are a bsent in the latter. ((C)Elsevier, Paris).