{"doi":"10.1002/cbic.202500186","title":"Conformational Constraint for Prevention of Aging of Organophosphate‐Inhibited Acetylcholinesterase","abstract":"The covalent inhibition of acetylcholinesterase (AChE) by organophosphate compounds (OPCs) prevents the hydrolysis of the neurotransmitter, acetylcholine, and results in overstimulation of muscarinic and nicotinic receptors leading to severe cholinergic crisis. To treat toxic exposure to OPCs, the focus has been on using reactivator compounds (e.g., oximes) to reverse the adduct formation in the enzyme's active site, and to release the regenerated, active form of AChE. However, the interaction between the OPC inhibitor and the enzyme is usually followed by a secondary dealkylative reaction in which the OPC \"ages\", that is, produces an oxyanion on the phosphoryl group that cannot be recovered with standard reactivators. The unexpected discovey that immobilization of AChE prevented aging of OPC adducts led to the hypothesis that the inhibition and recovery pathways in AChE could be regulated by allosteric effectors that bind to the enzyme at a distance away from the site of inhibition. To demonstrate this, resistance to aging was replicated using bifunctional crosslinking of AChE in solution. This work provides the foundation to expand these principles to other potential effectors.","journal":"ChemBioChem","year":2025,"id":528110,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290586,"name":"Ilya Trakht","orcid":null,"position":1,"is_corresponding":false},{"id":585685,"name":"Stevan Pecic","orcid":"0000-0002-3706-8768","position":2,"is_corresponding":false},{"id":521195,"name":"Alison Rinderspacher","orcid":"0000-0001-6840-8422","position":3,"is_corresponding":false},{"id":1405500,"name":"Laura Schneider","orcid":"0000-0002-1492-8550","position":4,"is_corresponding":false},{"id":104015,"name":"Donald W. Landry","orcid":"0000-0003-4046-5665","position":5,"is_corresponding":false},{"id":875173,"name":"Milan N. Stojanović","orcid":"0000-0001-6340-0982","position":6,"is_corresponding":false},{"id":442225,"name":"Francine S. Katz","orcid":"0000-0002-4481-6736","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:50:44.062153Z","pmid":"40211098","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}