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 journalArticle

216 Citations (Scopus)

Abstract

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
Volume9
Issue number6
StatePublished - 2000

Fingerprint

Acetylcholinesterase
Drosophila melanogaster
Vertebrates
Insects
Enzymes
Catalytic Domain
Aminacrine
Torpedo
Charge distribution
Fish
Conformations
Fishes
Trajectories

Keywords

  • Anticholinesterase
  • Insect acetylcholinesterase
  • Insecticide
  • Insecticide resistance

ASJC Scopus subject areas

  • Biochemistry

Cite this

Harel, M., Kryger, G., Rosenberry, T. L., Mallender, W. D., Lewis, T., Fletcher, R. J., ... Sussman, J. L. (2000). Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors. Protein Science, 9(6), 1063-1072.

Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors. / Harel, Michal; Kryger, Gitay; Rosenberry, Terrone L.; Mallender, William D.; Lewis, Terence; Fletcher, Rodney J.; Guss, J. Mitchell; Silman, Israel; Sussman, Joel L.

In: Protein Science, Vol. 9, No. 6, 2000, p. 1063-1072.

Research output: Contribution to journalArticle

Harel, M, Kryger, G, Rosenberry, TL, Mallender, WD, Lewis, T, Fletcher, RJ, Guss, JM, Silman, I & Sussman, JL 2000, 'Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors', Protein Science, vol. 9, no. 6, pp. 1063-1072.
Harel M, Kryger G, Rosenberry TL, Mallender WD, Lewis T, Fletcher RJ et al. Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors. Protein Science. 2000;9(6):1063-1072.
Harel, Michal ; Kryger, Gitay ; Rosenberry, Terrone L. ; Mallender, William D. ; Lewis, Terence ; Fletcher, Rodney J. ; Guss, J. Mitchell ; Silman, Israel ; Sussman, Joel L. / Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors. In: Protein Science. 2000 ; Vol. 9, No. 6. pp. 1063-1072.
@article{9846c1c2aa034624afbb31fc94a7c36d,
title = "Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors",
abstract = "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 {\AA} 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 {\AA} 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.",
keywords = "Anticholinesterase, Insect acetylcholinesterase, Insecticide, Insecticide resistance",
author = "Michal Harel and Gitay Kryger and Rosenberry, {Terrone L.} and Mallender, {William D.} and Terence Lewis and Fletcher, {Rodney J.} and Guss, {J. Mitchell} and Israel Silman and Sussman, {Joel L.}",
year = "2000",
language = "English (US)",
volume = "9",
pages = "1063--1072",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "6",

}

TY - JOUR

T1 - Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors

AU - Harel, Michal

AU - Kryger, Gitay

AU - Rosenberry, Terrone L.

AU - Mallender, William D.

AU - Lewis, Terence

AU - Fletcher, Rodney J.

AU - Guss, J. Mitchell

AU - Silman, Israel

AU - Sussman, Joel L.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Anticholinesterase

KW - Insect acetylcholinesterase

KW - Insecticide

KW - Insecticide resistance

UR - http://www.scopus.com/inward/record.url?scp=0033945085&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033945085&partnerID=8YFLogxK

M3 - Article

VL - 9

SP - 1063

EP - 1072

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 6

ER -