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

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

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

Artikel/kapitelEngelska2016

Förlag, utgivningsår, omfång ...

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

Nummerbeteckningar

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

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:ref swepub-contenttype
Ämneskategori:art swepub-publicationtype

Anmärkningar

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.

Ämnesord och genrebeteckningar

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

Biuppslag (personer, institutioner, konferenser, titlar ...)

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

Sammanhörande titlar

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

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Av författaren/redakt...: Allgardsson, And ...; Berg, Lotta; Akfur, Christine; Hörnberg, Andrea ...; Worek, Franz; Linusson, Anna; visa fler...; Ekström, Fredrik ...; visa färre...

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Av lärosätet: RISE; Umeå universitet

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