PDBsum entry 2jgi

Hydrolase

PDB id: 2jgi

Contents

Protein chains

535 a.a. *

Ligands

NAG

AE3

Waters ×60

* Residue conservation analysis

PDB id:

2jgi

Name:

Hydrolase

Title:

Crystal structure of mouse acetylcholinesterase inhibited by non-aged diisopropyl fluorophosphate (dfp)

Structure:

Acetylcholinesterase. Chain: a, b. Fragment: catalytic domain, residues 32-574. Synonym: ache. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f.

Resolution:

2.90Å R-factor: 0.204 R-free: 0.242

Authors:

A.Hornberg,A.-K.Tunemalm,F.Ekstrom

Key ref:

A.Hörnberg et al. (2007). Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state. Biochemistry, 46, 4815-4825. PubMed id: 17402711

Date:

13-Feb-07 Release date: 17-Apr-07

Protein chains

P21836  (ACES_MOUSE) -  Acetylcholinesterase from Mus musculus

Seq: 614 a.a.

Struc: 535 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 + H(+)

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

reference

Biochemistry 46:4815-4825 (2007)

PubMed id: 17402711

Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state.

A.Hörnberg, A.K.Tunemalm, F.Ekström.

ABSTRACT

Organophosphorus compounds (OPs), such as nerve agents and a group of insecticides, irreversibly inhibit the enzyme acetylcholinesterase (AChE) by a rapid phosphorylation of the catalytic Ser203 residue. The formed AChE-OP conjugate subsequently undergoes an elimination reaction, termed aging, that results in an enzyme completely resistant to oxime-mediated reactivation by medical antidotes. In this study, we present crystal structures of the non-aged and aged complexes between Mus musculus AChE (mAChE) and the nerve agents sarin, VX, and diisopropyl fluorophosphate (DFP) and the OP-based insecticides methamidophos (MeP) and fenamiphos (FeP). Non-aged conjugates of MeP, sarin, and FeP and aged conjugates of MeP, sarin, and VX are very similar to the noninhibited apo conformation of AChE. A minor structural change in the side chain of His447 is observed in the non-aged conjugate of VX. In contrast, an extensive rearrangement of the acyl loop region (residues 287-299) is observed in the non-aged structure of DFP and in the aged structures of DFP and FeP. In the case of FeP, the relatively large substituents of the phosphorus atom are reorganized during aging, providing a structural support of an aging reaction that proceeds through a nucleophilic attack on the phosphorus atom. The FeP aging rate constant is 14 times lower than the corresponding constant for the structurally related OP insecticide MeP, suggesting that tight steric constraints of the acyl pocket loop preclude the formation of a trigonal bipyramidal intermediate.