2JGJ

Crystal structure of mouse acetylcholinesterase inhibited by aged methamidophos

Summary for 2JGJ

• Entry DOI: 10.2210/pdb2jgj/pdb
• Related: 1C2B 1C2O 1J06 1J07 1KU6 1MAA 1MAH 1N5M 1N5R 1Q83 1Q84 2C0P 2C0Q 2H9Y 2HA0 2HA2 2HA3 2HA4 2HA5 2HA6 2HA7 2JEY 2JEZ 2JF0 2JGE 2JGF 2JGG 2JGH 2JGI 2JGK 2JGL 2JGM
• Descriptor: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-(2-ETHOXYETHOXY)ETHANOL, ... (5 entities in total)
• Functional Keywords: aging, synapse, membrane, hydrolase, methamidophos, serine esterase, neurotransmitter degradation
• Biological source: MUS MUSCULUS (MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 121484.89

Authors

Hornberg, A.,Tunemalm, A.-K.,Ekstrom, F. (deposition date: 2007-02-13, release date: 2007-04-17, Last modification date: 2023-12-13)

Primary citation

Hornberg, A.,Tunemalm, A.-K.,Ekstrom, F.
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-, 2007

PubMed 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.

PubMed: 17402711
DOI: 10.1021/BI0621361

Experimental method

X-RAY DIFFRACTION (2.5 Å)