7R2F

Structure of tabun inhibited acetylcholinesterase in complex with 2-((hydroxyimino)methyl)-1-(5-(4-methyl-3-nitrobenzamido)pentyl)pyridinium

Summary for 7R2F

• Entry DOI: 10.2210/pdb7r2f/pdb
• Related: 7QYN 7R02 7R0A 7R3C 7R4E
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-methyl-3-nitro-~{N}-[(2~{E},4~{E})-5-[2-[(oxidanylamino)methyl]pyridin-1-yl]penta-2,4-dienyl]benzamide, ... (6 entities in total)
• Functional Keywords: hydrolase, complex, tabun phosphylated, reactivator
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 123050.94

Authors

Forsgren, N.,Lindgren, C.,Edvinsson, L.,Linusson, A.,Ekstrom, F. (deposition date: 2022-02-04, release date: 2022-04-27, Last modification date: 2024-01-31)

Primary citation

Lindgren, C.,Forsgren, N.,Hoster, N.,Akfur, C.,Artursson, E.,Edvinsson, L.,Svensson, R.,Worek, F.,Ekstrom, F.,Linusson, A.
Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.
Chemistry, 28:e202200678-e202200678, 2022

PubMed Abstract: Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

PubMed: 35420233
DOI: 10.1002/chem.202200678

Experimental method

X-RAY DIFFRACTION (2.3 Å)