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PDBsum entry 2cmf
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References listed in PDB file
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Key reference
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Title
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Complexes of alkylene-Linked tacrine dimers with torpedo californica acetylcholinesterase: binding of bis5-Tacrine produces a dramatic rearrangement in the active-Site gorge.
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Authors
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E.H.Rydberg,
B.Brumshtein,
H.M.Greenblatt,
D.M.Wong,
D.Shaya,
L.D.Williams,
P.R.Carlier,
Y.P.Pang,
I.Silman,
J.L.Sussman.
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Ref.
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J Med Chem, 2006,
49,
5491-5500.
[DOI no: ]
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PubMed id
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Abstract
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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.
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