Structure Report for: 2W6C

Paz, A., Xie, Q., Greenblatt, H.M., Fu, W., Tang, Y., Silman, I., Qiu, Z., Sussman, J.L.

Title: The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad
Paz A, Xie Q, Greenblatt HM, Fu W, Tang Y, Silman I, Qiu Z, Sussman JL
Ref: Journal of Medicinal Chemistry, 52:2543, 2009 : PubMed
Abstract


ESTHER: Paz_2009_J.Med.Chem_52_2543
PubMedSearch: Paz 2009 J.Med.Chem 52 2543
PubMedID: 19326912
Gene_locus related to this paper: torca-ACHE
Inhibitor(s) related to this paper: bis9-(-)-nor-meptazinol

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.