The Crystal Structure of a Complex of Acetylcholinesterase with a Bis-(−)-<i>nor</i>-meptazinol Derivative Reveals Disruption of the Catalytic Triad

A bis-(−)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Aβ peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 Å resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the “anionic” subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440Nε2, which is hydrogen-bonded to Ser200Oγ in the native enzyme. The second nor-meptazinol binds at the peripheral “anionic” site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(−)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.