Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors

Michal Harel, Gitay Kryger, Terrone L. Rosenberry, William D. Mallender, Terence Lewis, Rodney J. Fletcher, J. Mitchell Guss, Israel Silman, Joel L. Sussman

Research output: Contribution to journalArticlepeer-review

239 Scopus citations


We have crystallized Drosophila melanogaster acetylcholinesterase and solved the structure of the native enzyme and of its complexes with two potent reversible inhibitors, 1,2,3,4-tetrahydro-N-(phenylmethyl)-9- acridinamine and 1,2,3,4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine- all-three at 2.7 Å resolution. The refined structure of D. melanogaster acetylcholinesterase is similar to that of vertebrate acetylcholinesterases, for example, human, mouse, and fish, in its overall fold, charge distribution, and deep active-site gorge, but some of the surface loops deviate by up to 8 Å from their position in the vertebrate structures, and the C-terminal helix is shifted substantially. The active-site gorge of the insect enzyme is significantly narrower than that of Torpedo californica ACHE, and its trajectory is shifted several angstroms. The volume of the lower part of the gorge of the insect enzyme is ~50% of that of the vertebrate enzyme. Upon binding of either of the two inhibitors, nine aromatic side chains within the active-site gorge change their conformation so as to interact with the inhibitors. Some differences in activity and specificity between the insect and vertebrate enzymes can be explained by comparison of their three-dimensional structures.

Original languageEnglish (US)
Pages (from-to)1063-1072
Number of pages10
JournalProtein Science
Issue number6
StatePublished - 2000


  • Anticholinesterase
  • Insect acetylcholinesterase
  • Insecticide
  • Insecticide resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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