Cassidy MS

References (2)

Title : Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface - Franklin_2016_Proteins_84_1246
Author(s) : Franklin MC , Rudolph MJ , Ginter C , Cassidy MS , Cheung J
Ref : Proteins , 84 :1246 , 2016
Abstract : Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. (c) 2016 Wiley Periodicals, Inc.
ESTHER : Franklin_2016_Proteins_84_1246
PubMedSearch : Franklin_2016_Proteins_84_1246
PubMedID: 27191504
Gene_locus related to this paper: human-ACHE

Title : Structures of human acetylcholinesterase in complex with pharmacologically important ligands - Cheung_2012_J.Med.Chem_55_10282
Author(s) : Cheung J , Rudolph MJ , Burshteyn F , Cassidy MS , Gary EN , Love J , Franklin MC , Height JJ
Ref : Journal of Medicinal Chemistry , 55 :10282 , 2012
Abstract : Human acetylcholinesterase (AChE) is a significant target for therapeutic drugs. Here we present high resolution crystal structures of human AChE, alone and in complexes with drug ligands; donepezil, an Alzheimer's disease drug, binds differently to human AChE than it does to Torpedo AChE. These crystals of human AChE provide a more accurate platform for further drug development than previously available.
ESTHER : Cheung_2012_J.Med.Chem_55_10282
PubMedSearch : Cheung_2012_J.Med.Chem_55_10282
PubMedID: 23035744
Gene_locus related to this paper: human-ACHE