7R3C
VX-inhibited acetylcholinesterase in complex with 2-((hydroxyimino)methyl)-1-(5-(4-methyl-3-nitrobenzamido)pentyl)pyridinium
Summary for 7R3C
| Entry DOI | 10.2210/pdb7r3c/pdb |
| Related | 7QYN 7R02 7R0A 7R2F 7R4E |
| Descriptor | Acetylcholinesterase, 4-methyl-3-nitro-~{N}-[(2~{E},4~{E})-5-[2-[(oxidanylamino)methyl]pyridin-1-yl]penta-2,4-dienyl]benzamide, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total) |
| Functional Keywords | hydrolase, ternary complex, reactivator |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 122556.32 |
| Authors | Forsgren, N.,Lindgren, C.,Edvinsson, L.,Linusson, A.,Ekstrom, F. (deposition date: 2022-02-07, 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 Cited by 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: 35420233DOI: 10.1002/chem.202200678 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.40000421983 Å) |
Structure validation
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