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PDBsum entry 2w6c
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References listed in PDB file
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Key reference
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Title
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The crystal structure of a complex of acetylcholinesterase with a bis-(-)-Nor-Meptazinol derivative reveals disruption of the catalytic triad.
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Authors
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A.Paz,
Q.Xie,
H.M.Greenblatt,
W.Fu,
Y.Tang,
I.Silman,
Z.Qiu,
J.L.Sussman.
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Ref.
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J Med Chem, 2009,
52,
2543-2549.
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PubMed id
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Abstract
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A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked
by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that
inhibits both catalytic activity and Abeta peptide aggregation. The crystal
structure of its complex with Torpedo californica acetylcholinesterase was
determined to 2.7 A resolution. The ligand spans the active-site gorge, with one
nor-meptazinol moiety bound at the "anionic" subsite of the active site,
disrupting the catalytic triad by forming a hydrogen bond with
His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) in the native
enzyme. The second nor-meptazinol binds at the peripheral "anionic" site at the
gorge entrance. A number of GOLD models of the complex, using both native TcAChE
and the protein template from the crystal structure of the
bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray
structure than a previous model obtained using the mouse enzyme structure. These
findings may facilitate rational design of new meptazinol-based
acetylcholinesterase inhibitors.
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