1zgc

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Template:STRUCTURE 1zgc

Contents

Crystal Structure of Torpedo Californica Acetylcholinesterase in Complex With an (RS)-Tacrine(10)-Hupyridone Inhibitor.

Publication Abstract from PubMed

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 in trigonal Torpedo californica AChE (TcAChE) crystals, and the X-ray structure of the resulting complex was solved to 2.30 A 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 in 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.

Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase., Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL, J Am Chem Soc. 2005 Aug 10;127(31):11029-36. PMID:16076210

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

1zgc is a 2 chain structure with sequence from Torpedo californica. Full crystallographic information is available from OCA.

See Also

Reference

  • Haviv H, Wong DM, Greenblatt HM, Carlier PR, Pang YP, Silman I, Sussman JL. Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase. J Am Chem Soc. 2005 Aug 10;127(31):11029-36. PMID:16076210 doi:http://dx.doi.org/10.1021/ja051765f
  • Carlier PR, Du DM, Han Y, Liu J, Pang YP. Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2335-8. PMID:10476864
  • Wong DM, Greenblatt HM, Dvir H, Carlier PR, Han YF, Pang YP, Silman I, Sussman JL. Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity. J Am Chem Soc. 2003 Jan 15;125(2):363-73. PMID:12517147 doi:http://dx.doi.org/10.1021/ja021111w
  • Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL. The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design. J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:15563167 doi:http://dx.doi.org/10.1021/ja0466154

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