6U37

Structure of VX-phosphonylated hAChE in complex with oxime reactivator RS194B

Summary for 6U37

• Entry DOI: 10.2210/pdb6u37/pdb
• Descriptor: Acetylcholinesterase, O-ETHYLMETHYLPHOSPHONIC ACID ESTER GROUP, (2E)-N-[2-(azepan-1-yl)ethyl]-2-(hydroxyimino)acetamide, ... (6 entities in total)
• Functional Keywords: oxime reactivator complex, vx-phosphonylated conjugate, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121805.05

Authors

Kovalevsky, A.,Gerlits, O.,Radic, Z. (deposition date: 2019-08-21, release date: 2020-02-12, Last modification date: 2024-10-30)

Primary citation

Gorecki, L.,Gerlits, O.,Kong, X.,Cheng, X.,Blumenthal, D.K.,Taylor, P.,Ballatore, C.,Kovalevsky, A.,Radic, Z.
Rational design, synthesis, and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase.
J.Biol.Chem., 295:4079-4092, 2020

PubMed Abstract: Organophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are nonproductive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE, here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved reactivation of diverse OP-human AChE conjugates. Oxime group reorientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity.

PubMed: 32019865
DOI: 10.1074/jbc.RA119.012400

Experimental method

X-RAY DIFFRACTION (2.25 Å)