4BBZ

Structure of human butyrylcholinesterase inhibited by CBDP (2-min soak): Cresyl-phosphoserine adduct

Summary for 4BBZ

• Entry DOI: 10.2210/pdb4bbz/pdb
• Related: 1EHO 1EHQ 1KCJ 1P0I 1P0M 1P0P 1P0Q 1XLU 1XLV 1XLW 2J4C 2WID 2WIF 2WIG 2WIJ 2WIK 2WIL 2WSL 2XMB 2XMC 2XMD 2XMG 2XQF 2XQG 2XQI 2XQJ 2XQK 2Y1K 4AQD 4AXB 4B0O 4B0P 4BC0 4BC1
• Descriptor: CHOLINESTERASE, beta-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[beta-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: hydrolase, acetylcholinesterase, nerve transmission, inhibition, alpha-beta hydrolase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 62575.42

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 (2.7 Å)