Dawn Wong - 3D structure of Torpedo californica acetylcholinesterase complexed with Huprine X at 2.1 Å resolution: kinetic and molecular dynamic correlates

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  Publication Details (including relevant citation   information):

  Dvir, H.; Wong, D. M.; Harel, M.; Barril, X.;   Orozco, M.; Luque, F. J.; Munoz-Torrero, D.; Camps, P.;   Rosenberry, T. L.; Silman, I.; Sussman, J. L.

  3D structure of Torpedo californica acetylcholinesterase   complexed with Huprine X at 2.1 A resolution: kinetic and   molecular dynamic correlates.

  Biochemistry 2002, 41, 2970-2981.

  PMID: 11863435. http://dx.doi.org/10.1021/bi011652i


  Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with   one of the highest affinities reported for a reversible   inhibitor. It is a synthetic hybrid that contains the   4-aminoquinoline substructure of one anti-Alzheimer drug,   tacrine, and a carbobicyclic moiety resembling that of another   AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X   with Torpedo californica AChE yielded crystals whose 3D structure   was determined to 2.1 Å resolution. The inhibitor binds to the   anionic site and also hinders access to the esteratic site. Its   aromatic portion occupies the same binding site as tacrine,   stacking between the aromatic rings of Trp84 and Phe330, whereas   the carbobicyclic unit occupies the same binding pocket as   (-)-huperzine A. Its chlorine substituent was found to lie in a   hydrophobic pocket interacting with rings of the aromatic   residues Trp432 and Phe330 and with the methyl groups of Met436   and Ile439. Steady-state inhibition data show that huprine X   binds to human AChE and Torpedo AChE 28- and 54-fold,   respectively, more tightly than tacrine. This difference stems   from the fact that the aminoquinoline moiety of huprine X makes   interactions similar to those made by tacrine, but additional   bonds to the enzyme are made by the huperzine-like substructure   and the chlorine atom. Furthermore, both tacrine and huprine X   bind more tightly to Torpedo than to human AChE, suggesting that   their quinoline substructures interact better with Phe330 than   with Tyr337, the corresponding residue in the human AChE   structure. Both (-)-huperzine A and huprine X display slow   binding properties, but only binding of the former causes a   peptide flip of Gly117.

  Address (URL): http://dx.doi.org/10.1021/bi011652i