Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

Conformations of C? backbones in X-ray structures most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar that the native hAChE. One exceptions is structure diethylphosphoryl-hAChE conjugate, where stabilization a large ethoxy group into acyl pocket (AP) hAChE-triggered notable loop distortions and consequential dissociation hAChE homodimer. Recently, six conjugated with OP nerve agents A-type, Novichoks, deposited PDB. In this study we analyzed backbone conformation shifts those structures, as well OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite snug fit substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected their backbones. Small magnitudes observed due 1.2–2.4 Å shift entire away from AP. It thus appears small AP AChEs can accommodate, without distortion, size or butyryl groups, provided “pulled” This observation has practical consequences structure-based design nucleophilic reactivation antidotes definition AChE specificity relies its