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Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, 5514-5519 p.Article in journal (Refereed) Published
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Text
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 113, no 20, 5514-5519 p.
Keyword [en]
acetylcholinesterase, density functional theory, crystallography, nerve agent, reactivation
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-121442DOI: 10.1073/pnas.1523362113ISI: 000375977600028PubMedID: 27140636OAI: oai:DiVA.org:umu-121442DiVA: diva2:942222
Available from: 2016-06-23 Created: 2016-06-02 Last updated: 2017-01-11Bibliographically approved
In thesis
1. Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase
Open this publication in new window or tab >>Exploring non-covalent interactions between drug-like molecules and the protein acetylcholinesterase
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
En studie av icke-kovalenta interaktioner mellan läkemedelslika molekyler och proteinet acetylkolinesteras
Abstract [en]

The majority of drugs are small organic molecules, so-called ligands, that influence biochemical processes by interacting with proteins. The understanding of how and why they interact and form complexes is therefore a key component for elucidating the mechanism of action of drugs. The research presented in this thesis is based on studies of acetylcholinesterase (AChE). AChE is an essential enzyme with the important function of terminating neurotransmission at cholinergic synapses. AChE is also the target of a range of biologically active molecules including drugs, pesticides, and poisons. Due to the molecular and the functional characteristics of the enzyme, it offers both challenges and possibilities for investigating protein-ligand interactions. In the thesis, complexes between AChE and drug-like ligands have been studied in detail by a combination of experimental techniques and theoretical methods. The studies provided insight into the non-covalent interactions formed between AChE and ligands, where non-classical CH∙∙∙Y hydrogen bonds (Y = O or arene) were found to be common and important. The non-classical hydrogen bonds were characterized by density functional theory calculations that revealed features that may provide unexplored possibilities in for example structure-based design. Moreover, the study of two enantiomeric inhibitors of AChE provided important insight into the structural basis of enthalpy-entropy compensation. As part of the research, available computational methods have been evaluated and new approaches have been developed. This resulted in a methodology that allowed detailed analysis of the AChE-ligand complexes. Moreover, the methodology also proved to be a useful tool in the refinement of X-ray crystallographic data. This was demonstrated by the determination of a prereaction conformation of the complex between the nerve-agent antidote HI-6 and AChE inhibited by the nerve agent sarin. The structure of the ternary complex constitutes an important contribution of relevance for the design of new and improved drugs for treatment of nerve-agent poisoning. The research presented in the thesis has contributed to the knowledge of AChE and also has implications for drug discovery and the understanding of biochemical processes in general.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 76 p.
Keyword
acetylcholinesterase, drug discovery, density functional theory, hydrogen bond, nerve-agent antidote, non-covalent interaction, protein-ligand complex, structure-based design, thermodynamics, X-ray crystallography
National Category
Chemical Sciences
Research subject
läkemedelskemi
Identifiers
urn:nbn:se:umu:diva-129900 (URN)978-91-7601-644-2 (ISBN)
Public defence
2017-02-03, Stora hörsalen (KB.E3.03), KBC-huset, Umeå universitet, Umeå, 10:00 (English)
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Available from: 2017-01-13 Created: 2017-01-10 Last updated: 2017-01-13Bibliographically approved

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