9SCM

Crystal structure of Tc AChE with reactivator JDS364 Orthorhombic

This is a non-PDB format compatible entry.

Summary for 9SCM

• Entry DOI: 10.2210/pdb9scm/pdb
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: complex, reactivator jds364, orthorhombic, hydrolase
• Biological source: Tetronarce californica (Pacific electric ray)
• Total number of polymer chains: 2
• Total formula weight: 121986.65

Authors

de la Mora, E.,De Sousa, J.,Weik, M.,Nachon, F.,Baati, R.,Dias, J. (deposition date: 2025-08-11, release date: 2026-06-10, Last modification date: 2026-06-17)

Primary citation

De Sousa, J.,Calas, A.G.,De La Mora, E.,Landry, C.,Hanak, A.S.,Maryan-Instone, A.,Gastellier, A.J.,Coisne, C.,Courageux, C.,Hachani, J.,Gosselet, F.,Dehouck, M.P.,Rousseau, C.,Timperley, C.M.,Weik, M.,Nachon, F.,Brown, R.C.D.,Baati, R.,Dias, J.
Design, synthesis and evaluation of an uncharged broad spectrum quinoline-oxime hybrid for the reactivation of nerve agent-inhibited human acetylcholinesterase.
Eur.J.Med.Chem., 316:119023-119023, 2026

PubMed Abstract: Organophosphorus nerve agents exert their acute toxicity by irreversibly inhibiting acetylcholinesterase (AChE), yet currently deployed oxime reactivators exhibit limited efficacy in the central nervous system due to poor blood-brain barrier (BBB) penetration. Addressing this limitation remains a critical challenge in the treatment of nerve agent exposure. We report the design, synthesis, and evaluation of JDS364, an uncharged hybrid oxime reactivator combining a quinoline-based peripheral site ligand with a 3-hydroxypyridinealdoxime nucleophile. In vitro studies using human AChE inhibited by surrogates of G- and V-series nerve agents demonstrated that JDS364 possesses broad-spectrum reactivation activity, notably achieving a 300-fold increase in reactivation efficiency (k) over the clinical benchmark obidoxime against tabun-like inhibited hAChE. Evaluation in a human in vitro BBB co-culture model revealed that JDS364 exhibits high permeability, significantly outperforming clinically used quaternary oximes and exceeding the flux of earlier-generation uncharged hybrids. Ex vivo functional profiling studies in mice confirmed rapid systemic availability and significant protection against paraoxon challenge (Protective Index = 6.7 when combined with atropine), though a narrower therapeutic window was observed compared to clinical standards. X-ray crystallographic analysis of JDS364 bound to human AChE uncovered ligand-induced conformational plasticity, providing the first structural evidence of an opening of a "backdoor" via Tyr449 rearrangement in the 20 Å deep active site gorge. This confirms the hypothesis of enzyme "breathing" motions and validates alternative diffusion pathways for reactivation. These findings establish JDS364 as a mechanistically significant, CNS-accessible lead that defines a new structural paradigm for the development of next-generation countermeasures.

PubMed: 42241775
DOI: 10.1016/j.ejmech.2026.119023

Experimental method

X-RAY DIFFRACTION (2.4 Å)