STRUCTURE AND INTERACTIONS OF A COMPLEX OF SNAKE VENOM TOXIN AND ACETYLCHOLINESTERASE. Michal Harel¹, Gerard J Kleywegt², Raimond BG Ravelli³, Israel Silman⁴, Joel L Sussman¹. ¹Dept of Structural Biology, Weizmann Inst of Science, Rehovot, Israel; ²Dept of Molecular Biology, Uppsala University, Uppsala, Sweden; ³Dept of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Res, Utrecht, The Netherlands; ⁴Dept of Neurobiology, Weizmann Inst of Science, Rehovot, Israel; ⁵Dept of Biology, Brookhaven National Lab, Upton, NY, USA

The selective inhibition of acetylcholinesterase (AChE) by the snake toxin fasciculin-II was analysed using the 3D structure at 3.0 Å resolution of the 1:1 complex of the two proteins. The x-ray structure of the complex shows the 3-fingered toxin to be situated at the opening of the active-site gorge of the enzyme at the proposed peripheral anionic binding site. The toxin is interacting with AChE through an unusually large contact area and through a number of residues which are unique to fasciculin(FAS) or rare in other 3-fingered toxins. Two of the three tips of the toxin show multiple interactions with the enzyme with one tip blocking the entrance to the active-site gorge and the other interacting with the thin wall of the gorge. Both AChE and FAS maintain their 3D structures upon complexation. The interactions between FAS and AChE are mainly hydrophobic and the crucial role of aromatic residues in the activity of AChE is demonstrated again in the fact that cholinesterases lacking 2 aromatic residues in their peripheral anionic site show reduced affinity to FAS.