Dawn Wong - Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase

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      Publication Details (including relevant citation   information):

      Haviv, H.; Wong, D. M.; Greenblatt, H. M.;   Carlier, P. R.; Pang, Y.-P.; Silman, I.; Sussman, J. L. Crystal   packing mediates enantioselective ligand recognition at the   peripheral site of acetylcholinesterase. Journal of the   American Chemical Society 2005, 127,   11029-11036.

      PMID: 16076210. http://dx.doi.org/10.1021/ja051765f



      Recently, alkylene-linked heterodimers of tacrine   (1) and 5-amino-5,6,7,8-tetrahydroquinolinone   (2, hupyridone) were shown to exhibit higher   acetylcholinesterase (AChE) inhibition than either monomeric   1 or 2. Such inhibitors are   potential drug candidates for ameliorating the cognitive   decrements in early Alzheimer patients. In an attempt to   understand the inhibition mechanism of one such dimer,   (RS)-(±)-N-9-(1,2,3,4-tetrahydroacridinyl)-N'-5-[5,6,7,8-tetrahydro-2'(1'H)-quinolinonyl]-1,10-diaminodecane   [(RS)-(±)-3] bisoxalate, the   racemate was soaked into trigonal Torpedo californica  AChE (TcAChE) crystals, and the X-ray structure of the   resulting complex was solved to 2.30 Å resolution. Its structure   revealed the 1 unit bound to the "anionic"   subsite of the active site, near the bottom of the active-site   gorge, as seen for the 1/TcAChE   complex. Interestingly, only the (R)-enantiomer of the   2 unit was seen in the peripheral "anionic" site   (PAS) at the top of the gorge, and was hydrogen-bonded to the   side chains of residues belonging to an adjacent,   symmetry-related AChE molecule covering the gorge entrance. When   the same racemate was soaked into orthorhombic crystals of   TcAChE, in which the entrance to the gorge is more   exposed, the crystal structure of the corresponding complex   revealed no substantial enantiomeric selectivity. This   observation suggests that the apparent enantiomeric selectivity   of trigonal crystals of TcAChE for   (R)-3 is mainly due to crystal packing,   resulting in preferential binding of one enantiomeric inhibitor   both to its "host" enzyme and to its neighbor in the asymmetric   unit, rather than to steric constraints imposed by the geometry   of the active-site gorge.

      Address (URL): http://dx.doi.org/10.1021/ja051765f