4BC1

Structure of mouse acetylcholinesterase inhibited by CBDP (30-min soak): cresyl-saligenin-phosphoserine adduct

Summary for 4BC1

• Entry DOI: 10.2210/pdb4bc1/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 2JGJ 2JGK 2JGL 2JGM 2WHP 2WHQ 2WHR 2WLS 2WU3 2WU4 2XUD 2XUF 2XUG 2XUH 2XUI 2XUJ 2XUK 2XUO 2XUP 2XUQ 4A16 4A23 4ARA 4ARB 4B7Z 4B80 4B81 4B82 4B83 4B84 4B85 4BBZ 4BC0
• Descriptor: ACETYLCHOLINESTERASE, O-CRESYL-SALIGENIN PHOSPHATE, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: hydrolase, butyrylcholinesterase, nerve transmission, inhibitor, alpha-beta hydrolase
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 4
• Total formula weight: 243614.30

Authors

Carletti, E.,Colletier, J.-P.,Schopfer, L.M.,Santoni, G.,Masson, P.,Lockridge, O.,Nachon, F.,Weik, M. (deposition date: 2012-09-30, release date: 2013-02-06, Last modification date: 2024-10-23)

Primary citation

Carletti, E.,Colletier, J.-P.,Schopfer, L.M.,Santoni, G.,Masson, P.,Lockridge, O.,Nachon, F.,Weik, M.
Inhibition Pathways of the Potent Organophosphate Cbdp with Cholinesterases Revealed by X-Ray Crystallographic Snapshots and Mass Spectrometry
Chem.Res.Toxicol., 26:280-, 2013

PubMed Abstract: Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 Å snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H(2)(16)O or H(2)(18)O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP.

PubMed: 23339663
DOI: 10.1021/TX3004505

Experimental method

X-RAY DIFFRACTION (2.95 Å)