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

Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of...

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Autores principales:	Stephanie Luedtke, Celine Bojo, Yunshen Li, Emilio Luna, Bianca Pomar, Zoran Radić
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acetylcholinesterase organophosphate Novichok backbone conformation oxime reactivation oxime antidote Crystallography QD901-999
Acceso en línea:	https://doaj.org/article/94a5acd9271e4ecba05bfc956d24d0e3
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spelling	oai:doaj.org-article:94a5acd9271e4ecba05bfc956d24d0e32021-11-25T17:17:33ZBackbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition10.3390/cryst111112702073-4352https://doaj.org/article/94a5acd9271e4ecba05bfc956d24d0e32021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4352/11/11/1270https://doaj.org/toc/2073-4352Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.Stephanie LuedtkeCeline BojoYunshen LiEmilio LunaBianca PomarZoran RadićMDPI AGarticleacetylcholinesteraseorganophosphateNovichokbackbone conformationoxime reactivationoxime antidoteCrystallographyQD901-999ENCrystals, Vol 11, Iss 1270, p 1270 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acetylcholinesterase organophosphate Novichok backbone conformation oxime reactivation oxime antidote Crystallography QD901-999
spellingShingle	acetylcholinesterase organophosphate Novichok backbone conformation oxime reactivation oxime antidote Crystallography QD901-999 Stephanie Luedtke Celine Bojo Yunshen Li Emilio Luna Bianca Pomar Zoran Radić Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
description	Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.
format	article
author	Stephanie Luedtke Celine Bojo Yunshen Li Emilio Luna Bianca Pomar Zoran Radić
author_facet	Stephanie Luedtke Celine Bojo Yunshen Li Emilio Luna Bianca Pomar Zoran Radić
author_sort	Stephanie Luedtke
title	Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
title_short	Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
title_full	Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
title_fullStr	Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
title_full_unstemmed	Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition
title_sort	backbone conformation shifts in x-ray structures of human acetylcholinesterase upon covalent organophosphate inhibition
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/94a5acd9271e4ecba05bfc956d24d0e3
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_version_	1718412545913520128

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

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