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
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U2 - 10.1110/ps.9.6.1063
DO - 10.1110/ps.9.6.1063
M3 - Article
C2 - 10892800
AN - SCOPUS:0033945085
SN - 0961-8368
VL - 9
SP - 1063
EP - 1072
JO - Protein Science
JF - Protein Science
IS - 6
ER -