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

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Fältnamn	Indikatorer	Metadata
000		03961naa a2200481 4500
001		oai:DiVA.org:ri-434
003		SwePub
008		160623s2016 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:DiVA.org:umu-121442
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-4342 URI
024	7	a https://doi.org/10.1073/pnas.15233621132 DOI
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1214422 URI
040		a (SwePub)rid (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Allgardsson, Andersu FOI Swedish Defence Research Agency, Sweden4 aut
245	1 0	a Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6
264		c 2016-05-02
264	1	b National Academy of Sciences,c 2016
338		a print2 rdacarrier
520		a 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.
650	7	a NATURVETENSKAPx Kemi0 (SwePub)1042 hsv//swe
650	7	a NATURAL SCIENCESx Chemical Sciences0 (SwePub)1042 hsv//eng
653		a Acetylcholinesterase
653		a Crystallography
653		a Density functional theory
653		a Nerve agent
653		a Reactivation
700	1	a Berg, Lottau Umeå universitet,Kemiska institutionen,Umeå University, Sweden4 aut0 (Swepub:umu)loed0002
700	1	a Akfur, Christineu FOI Swedish Defence Research Agency, Sweden4 aut
700	1	a Hörnberg, Andreasu RISE,SP Processum4 aut0 (Swepub:ri)andreasho@ri.se
700	1	a Worek, Franzu Bundeswehr Institute of Pharmacology and Toxicology, Germany4 aut
700	1	a Linusson, Annau Umeå universitet,Kemiska institutionen,Umeå University, Sweden4 aut0 (Swepub:umu)analin99
700	1	a Ekström, Fredrik J.u FOI Swedish Defence Research Agency, Sweden4 aut
710	2	a FOI Swedish Defence Research Agency, Swedenb Kemiska institutionen4 org
773	0	t Proceedings of the National Academy of Sciences of the United States of Americad : National Academy of Sciencesg 113:20, s. 5514-5519q 113:20<5514-5519x 0027-8424x 1091-6490
856	4	u https://doi.org/10.1073/pnas.1523362113y Fulltext
856	4	u https://www.pnas.org/content/pnas/113/20/5514.full.pdf
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-434
856	4 8	u https://doi.org/10.1073/pnas.1523362113
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-121442

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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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