1odc

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Image:1odc.png

Template:STRUCTURE 1odc

Contents

STRUCTURE OF ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH N-4'-QUINOLYL-N'-9"-(1",2",3",4" -TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE AT 2.2A RESOLUTION

Publication Abstract from PubMed

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.

Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge., Rydberg EH, Brumshtein B, Greenblatt HM, Wong DM, Shaya D, Williams LD, Carlier PR, Pang YP, Silman I, Sussman JL, J Med Chem. 2006 Sep 7;49(18):5491-500. PMID:16942022

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

About this Structure

1odc is a 1 chain structure of Acetylcholinesterase with sequence from Torpedo californica. Full crystallographic information is available from OCA.

See Also

Reference

  • Rydberg EH, Brumshtein B, Greenblatt HM, Wong DM, Shaya D, Williams LD, Carlier PR, Pang YP, Silman I, Sussman JL. Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J Med Chem. 2006 Sep 7;49(18):5491-500. PMID:16942022 doi:http://dx.doi.org/10.1021/jm060164b
  • 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
  • Carlier PR, Chow ES, Han Y, Liu J, El Yazal J, Pang YP. Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions. J Med Chem. 1999 Oct 7;42(20):4225-31. PMID:10514292
  • Pang YP, Kozikowski AP. Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies. J Comput Aided Mol Des. 1994 Dec;8(6):669-81. PMID:7738603
  • Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031-5. PMID:8415649
  • Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991 Aug 23;253(5022):872-9. PMID:1678899

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