PDBsum entry 5bwc

Hydrolase/hydrolase inhibitor

PDB id: 5bwc

Contents

Protein chain

532 a.a.

Ligands

NAG ×2

HBP

Waters ×114

PDB id:

5bwc

Name:

Hydrolase/hydrolase inhibitor

Title:

Acetylcholinesterase (E.C. 3.1.1.7) from torpedo californica in complex with the bis-pyridinium oxime ortho-7

Structure:

Acetylcholinesterase. Chain: a. Synonym: ache. Ec: 3.1.1.7

Source:

Torpedo californica. Pacific electric ray. Organism_taxid: 7787

Resolution:

2.45Å R-factor: 0.243 R-free: 0.266

Authors:

P.M.Legler,C.B.Millard

Key ref:

P.M.Legler et al. (2015). A conformational change in the peripheral anionic site of Torpedo californica acetylcholinesterase induced by a bis-imidazolium oxime. Acta Crystallogr D Biol Crystallogr, 71, 1788-1798. PubMed id: 26327369 DOI: 10.1107/S1399004715011281

Date:

07-Jun-15 Release date: 09-Sep-15

Protein chain

P04058  (ACES_TETCF) -  Acetylcholinesterase from Tetronarce californica

Seq: 586 a.a.

Struc: 532 a.a.

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 + H(+)

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

reference

DOI no: 10.1107/S1399004715011281

Acta Crystallogr D Biol Crystallogr 71:1788-1798 (2015)

PubMed id: 26327369

A conformational change in the peripheral anionic site of Torpedo californica acetylcholinesterase induced by a bis-imidazolium oxime.

P.M.Legler, I.Soojhawon, C.B.Millard.

ABSTRACT

As part of ongoing efforts to design improved nerve agent antidotes, two X-ray crystal structures of Torpedo californica acetylcholinesterase (TcAChE) bound to the bis-pyridinium oxime, Ortho-7, or its experimental bis-imidazolium analogue, 2BIM-7, were determined. Bis-oximes contain two oxime groups connected by a hydrophobic linker. One oxime group of Ortho-7 binds at the entrance to the active-site gorge near Trp279, and the second binds at the bottom near Trp84 and Phe330. In the Ortho-7-TcAChE complex the oxime at the bottom of the gorge was directed towards the nucleophilic Ser200. In contrast, the oxime group of 2BIM-7 was rotated away from Ser200 and the oxime at the entrance induced a significant conformational change in the peripheral anionic site (PAS) residue Trp279. The conformational change alters the surface of the PAS and positions the imidazolium oxime of 2BIM-7 further from Ser200. The relatively weaker binding and poorer reactivation of VX-inhibited, tabun-inhibited or sarin-inhibited human acetylcholinesterase by 2BIM-7 compared with Ortho-7 may in part be owing to the unproductively bound states caught in crystallo. Overall, the reactivation efficiency of 2BIM-7 was comparable to that of 2-pyridine aldoxime methyl chloride (2-PAM), but unlike 2-PAM the bis-imidazolium oxime lacks a fixed charge, which may affect its membrane permeability.