ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Analysis of ligand recognition by choline O-acetyltransferase reveals thiol-reactive assay interference and weak ligand affinity in solution.The Journal of biological chemistry · 2026Article
- Acetylcholinesterase: Structure, dynamics, and interactions with organophosphorus compounds.Protein science : a publication of the Protein Society · 2025Review
- Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer's Disease.Molecules (Basel, Switzerland) · 2025Review
- Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach.Scientific reports · 2021Article
- Identification and Study of Biomarkers from Novichok-Inhibited Butyrylcholinesterase in Human Plasma.Molecules (Basel, Switzerland) · 2021Article
- A Comprehensive Review of Cholinesterase Modeling and Simulation.Biomolecules · 2021Review
- Molecular modeling-guided optimization of acetylcholinesterase reactivators: A proof for reactivation of covalently inhibited targets.European journal of medicinal chemistry · 2021Article
- Development of versatile and potent monoquaternary reactivators of acetylcholinesterase.Archives of toxicology · 2021Article
- Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase.Biomolecules · 2021Article
- Room temperature crystallography of human acetylcholinesterase bound to a substrate analogue 4K-TMA: Towards a neutron structure.Current research in structural biology · 2021Article
- Synthesis,Journal of enzyme inhibition and medicinal chemistry · 2020Article
- 1-(3-Biomolecules · 2020Article
- Quantum approach to the mechanism of monothiopyrophosphate isomerization.Journal of molecular modeling · 2019Article
- Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.The Journal of biological chemistry · 2019Article
- The structural and biochemical impacts of monomerizing human acetylcholinesterase.Protein science : a publication of the Protein Society · 2019Article
- Identification of new allosteric sites and modulators of AChE through computational and experimental tools.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet.Molecules (Basel, Switzerland) · 2017Article
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7 authors.
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Abstract
Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.
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