Dawn Wong - Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of bis(5)-tacrine produces a dramatic rearrangement in the active-site gorge

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  Publication Details (including relevant citation   information):

  Rydberg, E. H.; Brumshtein, B.; Greenblatt, H. M.; Wong,   D. M.; Shaya, D.; Williams, L. D.; Carlier, P. R.; Pang,   Y.-P.; Silman, I.; Sussman, J. L. Complexes of alkylene-linked   tacrine dimers with Torpedocalifornica  acetylcholinesterase: Binding of bis(5)-tacrine produces   a dramatic rearrangement in the active-site gorge. Journal of   Medicinal Chemistry 2006, 49, 5491-5500.




  The X-ray crystal structures were solved for complexes with   Torpedo californica acetylcholinesterase of two bivalent   tacrine derivative compounds in which the two tacrine rings were   separated by 5- and 7-carbon spacers. The derivative with the   7-carbon spacer spans the length of the active-site gorge, making   sandwich interactions with aromatic residues both in the   catalytic anionic site (Trp84 and Phe330) at the bottom of the   gorge and at the peripheral anionic site near its mouth (Tyr70   and Trp279). The derivative with the 5-carbon spacer interacts in   a similar manner at the bottom of the gorge, but the shorter   tether precludes a sandwich interaction at the peripheral anionic   site. Although the upper tacrine group does interact with Trp279,   it displaces the phenyl residue of Phe331, thus causing a major   rearrangement in the Trp279-Ser291 loop. The ability of this   inhibitor to induce large-scale structural changes in the   active-site gorge of acetylcholinesterase has significant   implications for structure-based drug design because such   conformational changes in the target enzyme are difficult to   predict and to model.

  Address (URL): http://dx.doi.org/10.1021/jm060164b