6G4N

Torpedo californica acetylcholinesterase bound to uncharged hybrid reactivator 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 2.2 of the entry. See complete history


Literature

Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.

Santoni, G.de Sousa, J.de la Mora, E.Dias, J.Jean, L.Sussman, J.L.Silman, I.Renard, P.Y.Brown, R.C.D.Weik, M.Baati, R.Nachon, F.

(2018) J Med Chem 61: 7630-7639

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00592
  • Primary Citation of Related Structures:  
    6FLD, 6FQN, 6G17, 6G4M, 6G4N, 6G4O, 6G4P

  • PubMed Abstract: 

    Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.


  • Organizational Affiliation

    Université Grenoble Alpes, CEA, CNRS, IBS , F-38000 Grenoble , France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholinesterase
A, B
537Tetronarce californicaMutation(s): 0 
EC: 3.1.1.7
UniProt
Find proteins for P04058 (Tetronarce californica)
Explore P04058 
Go to UniProtKB:  P04058
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04058
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.807α = 90
b = 107.208β = 90
c = 150.45γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French National Research AgencyFranceReAChE

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-29
    Type: Initial release
  • Version 1.1: 2018-09-26
    Changes: Data collection, Database references
  • Version 2.0: 2019-05-01
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Polymer sequence, Source and taxonomy, Structure summary
  • Version 2.1: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 2.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description, Structure summary