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spinqualitylabelsall models AChE complex with soman Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Acetylcholinesterase inhibited by nerve agent soman (see also AChE inhibitors and substrates, 2wfz, 2wg0, 2wg1, and 1cfj) Biological Function Acetylcholinesterase (AChE) is a key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, acetylcholine (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) nerve agents is attributed primarily to their being potent AChE inhibitors. Overview Organophosphorus (OP)acid anhydride nerve agents are potent inhibitors which rapidly phosphonylate AChE and then may undergo an internal dealkylation reaction (called "aging") to produce an OP-enzyme conjugate that cannot be reactivated. Reaction between Ser200OG and Soman, assuming an in-line attack by the OG, followed by spontaneous dealkylation of the O-pinacolyl group. To understand the basis for irreversible inhibition, we solved the structure of the aged conjugate obtained by reaction of Torpedo californica AChE (TcAChE) with O-pinacolylmethylphosphonofluoridate (soman) by X-ray crystallography to 2.2Å resolution. The highest positive difference density peak corresponded to the OP phosphorus and was located within covalent bonding distance of the active-site serine (S200). The OP-oxygen atoms are within hydrogen-bonding distance of four potential donors from catalytic subsites of the enzyme, suggesting that electrostatic forces significantly stabilize the aged enzyme. The methyl group of soman occupies the acyl binding pocket, bounded by Trp233, Phe288, and Phe290. The active sites of aged sarin-TcAChE (1cfj) and soman-TcAChE were essentially identical and provided structural models for the negatively charged, tetrahedral intermediate that occurs during deacylation with the natural substrate, acetylcholine.