Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Search: onr:"swepub:oai:DiVA.org:ri-434" > Structure of a prer...

1 of 1
Previous record
Next record
To hitlist

Details
MARC

Allgardsson, AndersFOI Swedish Defence Research Agency, Sweden (author)

Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

Article/chapterEnglish2016

Publisher, publication year, extent ...

2016-05-02
National Academy of Sciences,2016
printrdacarrier

Numbers

LIBRIS-ID:oai:DiVA.org:ri-434
https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-434URI
https://doi.org/10.1073/pnas.1523362113DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-121442URI

Supplementary language notes

Language:English
Summary in:English

Part of subdatabase

SwePubSwePub

Classification

Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
Acetylcholinesterase
Crystallography
Density functional theory
Nerve agent
Reactivation

Added entries (persons, corporate bodies, meetings, titles ...)

Berg, LottaUmeå universitet,Kemiska institutionen,Umeå University, Sweden(Swepub:umu)loed0002 (author)
Akfur, ChristineFOI Swedish Defence Research Agency, Sweden (author)
Hörnberg, AndreasRISE,SP Processum(Swepub:ri)andreasho@ri.se (author)
Worek, FranzBundeswehr Institute of Pharmacology and Toxicology, Germany (author)
Linusson, AnnaUmeå universitet,Kemiska institutionen,Umeå University, Sweden(Swepub:umu)analin99 (author)
Ekström, Fredrik J.FOI Swedish Defence Research Agency, Sweden (author)
FOI Swedish Defence Research Agency, SwedenKemiska institutionen (creator_code:org_t)

Related titles

In:Proceedings of the National Academy of Sciences of the United States of America: National Academy of Sciences113:20, s. 5514-55190027-84241091-6490

Internet link

Find in a library

Proceedings of the National Academy of Sciences of the United States of America (Search for host publication in LIBRIS)

To the university's database

1 of 1
Previous record
Next record
To hitlist

Find more in SwePub

By the author/editor: Allgardsson, And ...; Berg, Lotta; Akfur, Christine; Hörnberg, Andrea ...; Worek, Franz; Linusson, Anna; show more...; Ekström, Fredrik ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...

Articles in the publication: Proceedings of t ...

By the university: RISE; Umeå University

Search outside SwePub

Extend your search to:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se