Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products

Yvain Nicolet, Oksana Lockridge, Patrick Masson, Juan C. Fontecilla-Camps, Florian Nachon

Research output: Contribution to journalArticle

475 Citations (Scopus)

Abstract

Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser198 has been modeled as bound butyrate.

Original languageEnglish (US)
Pages (from-to)41141-41147
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number42
DOIs
StatePublished - Oct 17 2003

Fingerprint

Butyrylcholinesterase
Crystal structure
Substrates
Acetylcholinesterase
Torpedo
Butyrates
Poisons
Cholinesterases
Enzymes
Cocaine
Pesticides
Acetylcholine
Carrier concentration
Neurotransmitter Agents
Hydrolysis
Catalytic Domain
Esters
Theoretical Models
Electrons

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products. / Nicolet, Yvain; Lockridge, Oksana; Masson, Patrick; Fontecilla-Camps, Juan C.; Nachon, Florian.

In: Journal of Biological Chemistry, Vol. 278, No. 42, 17.10.2003, p. 41141-41147.

Research output: Contribution to journalArticle

Nicolet, Yvain ; Lockridge, Oksana ; Masson, Patrick ; Fontecilla-Camps, Juan C. ; Nachon, Florian. / Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 42. pp. 41141-41147.
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