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

We have crystallized Drosophila melanogaster acetylcholinesterase and solve d the structure of the native enzyme and of its complexes with two potent r eversible inhibitors, 1,2,3,4-tetrahydro-N-(phenylmethyl)-9-acridinamine an d 1,2,3,4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine-all three at 2. 7 Angstrom resolution. The refined structure of D. melanogaster acetylcholi nesterase is similar to that of vertebrate acetylcholinesterases, for examp le, human, mouse, and fish, in its overall fold, charge distribution, and d eep active-site gorge, but some of the surface loops deviate by up to 8 Ang strom 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 tr ajectory is shifted several angstroms. The volume of the lower part of the gorge of the insect enzyme is similar to 50% of that of the vertebrate enzy me. Upon binding of either of the two inhibitors, nine aromatic side chains within the active-site gorge change their conformation so as to interact w ith the inhibitors. Some differences in activity and specificity between th e insect and vertebrate enzymes can be explained by comparison of their thr ee-dimensional structures.