PDBsum entry 6fld

Hydrolase

PDB id: 6fld

Contents

Protein chain

532 a.a.

Ligands

NAG ×3

DQ5

1PG

EDO ×3

Metals

_CL ×5

Waters ×212

PDB id:

6fld

Name:

Hydrolase

Title:

Carbamylated t. Californica acetylcholineterase bound to uncharged hybrid reactivator 1

Structure:

Acetylcholinesterase. Chain: a. Synonym: ache. Engineered: yes

Source:

Tetronarce californica. Pacific electric ray. Organism_taxid: 7787. Gene: ache. Expressed in: tetronarce californica. Expression_system_taxid: 7787

Resolution:

2.40Å R-factor: 0.180 R-free: 0.210

Authors:

E.De La Mora,G.Santoni,J.De Souza,J.Sussman,I.Silman,R.Baati,M.Weik, F.Nachon

Key ref:

G.Santoni et al. (2018). Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents. J Med Chem, 61, 7630-7639. PubMed id: 30125110 DOI: 10.1021/acs.jmedchem.8b00592

Date:

25-Jan-18 Release date: 29-Aug-18

Protein chain

P04058  (ACES_TETCF) -  Acetylcholinesterase from Tetronarce californica

Seq: 586 a.a.

Struc: 532 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.1.7 - acetylcholinesterase.
• Reaction: acetylcholine + H2O = choline + acetate + H⁺

acetylcholine (Bound ligand (Het Group name = NAG) matches with 41.18% similarity) + H2O = choline + acetate (Bound ligand (Het Group name = EDO) matches with 60.00% similarity) + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.8b00592

J Med Chem 61:7630-7639 (2018)

PubMed id: 30125110

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

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

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.