title: The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad.
abstract: 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 Abeta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A 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 His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) 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.
authors.affiliation: Department of Structural Biology and Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Paz
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Harry M
authors.initials: HM
authors.lastname: Greenblatt
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.forename: Zhuibai
authors.initials: Z
authors.lastname: Qiu
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman