The structure of G117H mutant of butyrylcholinesterase: Nerve agents scavenger

Moshe Amitay, Avital Shurki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Organophosphate ester (OP) compounds are known for their ubiquitous use as insecticides. At the same time, these chemicals are highly toxic and can be used as nerve agents. G117H mutant of human Butyrylcholinesterase (BChE) was found to be capable of hydrolyzing certain OPs and protect against their toxicity. However, for therapeutic use, the rate of hydrolysis is too low. Its catalytic power can be improved by rational design, but the structure of the G117H mutant is first required. In this work, we determined, computationally, the three dimensional structure of the G117H BChE mutant. The structure was then validated by simulating acetylation of acetylthiocholine (ATC). Several plausible conformers of G117H BChE were examined but only the (62,-75) conformer fully reproduced catalytic effect. The (62,-75) conformer is, therefore, suggested as the structure adopted by the G117H BChE mutant. This conformer is shown to explain the loss of esterase activity observed for the G122H Acetylcholinesterase mutant together with its recovery when additional mutations are placed turning the enzyme also into an OP hydrolase. Furthermore, similarity of the structure to the structure of RNase A, which is known to hydrolyze the O-P bond in RNA, grants it further credibility and suggests a mechanism for the OP hydrolysis.

Original languageAmerican English
Pages (from-to)370-377
Number of pages8
JournalProteins: Structure, Function and Bioinformatics
Volume77
Issue number2
DOIs
StatePublished - 1 Nov 2009

Keywords

  • Butyrylcholinesterase
  • Empirical valence bond
  • Hydrolysis
  • Organophosphate esters
  • Serine esterases
  • Simulations

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