Hornberg_2007_Biochemistry_46_4815

Reference

Title : 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 - Hornberg_2007_Biochemistry_46_4815
Author(s) : Hornberg A , Tunemalm AK , Ekstrom F
Ref : Biochemistry , 46 :4815 , 2007
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.

PubMedSearch : Hornberg_2007_Biochemistry_46_4815
PubMedID: 17402711
Gene_locus related to this paper: mouse-ACHE

Related information

Inhibitor Fenamiphos
Gene_locus Fenamiphos    mouse-ACHE
Structure Fenamiphos    mouse-ACHE    2Y2U    2Y2V    2JGM    2JGL    2JGK    2JGE    2JGF    2JGI    2JGJ

Citations formats

Hornberg A, Tunemalm AK, Ekstrom F (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

Hornberg A, Tunemalm AK, Ekstrom F (2007)
Biochemistry 46 :4815