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PDBsum entry 1j07
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site.
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Authors
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Y.Bourne,
P.Taylor,
Z.Radić,
P.Marchot.
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Ref.
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EMBO J, 2003,
22,
1.
[DOI no: ]
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PubMed id
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Abstract
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The peripheral anionic site on acetylcholinesterase (AChE), located at the
active center gorge entry, encompasses overlapping binding sites for allosteric
activators and inhibitors; yet, the molecular mechanisms coupling this site to
the active center at the gorge base to modulate catalysis remain unclear. The
peripheral site has also been proposed to be involved in heterologous protein
associations occurring during synaptogenesis or upon neurodegeneration. A novel
crystal form of mouse AChE, combined with spectrophotometric analyses of the
crystals, enabled us to solve unique structures of AChE with a free peripheral
site, and as three complexes with peripheral site inhibitors: the
phenylphenanthridinium ligands, decidium and propidium, and the pyrogallol
ligand, gallamine, at 2.20-2.35 A resolution. Comparison with structures of AChE
complexes with the peptide fasciculin or with organic bifunctional inhibitors
unveils new structural determinants contributing to ligand interactions at the
peripheral site, and permits a detailed topographic delineation of this site.
Hence, these structures provide templates for designing compounds directed to
the enzyme surface that modulate specific surface interactions controlling
catalytic activity and non-catalytic heterologous protein associations.
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Figure 1.
Figure 1 PAS ligands (AChE inhibitors) used in this study.
Schematic drawings (from top to bottom) of the
phenylphenanthridinium ligands propidium (PI;
3,8-diamino-5[3'-(diethylmethylammonio) propyl]-6-phenyl
phenanthridinium) and decidium (DI; 3,8-diamino-5[10'-
(trimethyl-ammonio) decyl]-6-phenyl phenanthridinium), and of
the pyrogallol ligand gallamine (GAL;
2,2',2"-[1,2,3-benzene-triyltris(oxy)]tris[N,N,N-triethylethanamonium]).
PI and DI were diiodide salts and GAL was a triiodide.
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Figure 5.
Figure 5 Structural comparisons of the DI -mAChE complex with
the Fas2 -mAChE complex and the crystalline mAChE tetramer. (A)
Close-up view of a superimposition of the DI molecule (orange
bonds, blue nitrogen and red oxygen atoms) in the DI -mAChE
complex with the interacting central loop (loop II) of Fas2
(yellow) bound to mAChE in the Fas2 -mAChE complex (1KU6),
according to all C[  ]atoms
of mAChE in the two structures. The Fas2 side chains that match
the structural determinants of the DI molecule are displayed as
green bonds. (B) Superimposition of the DI molecule (colored as
in A) in the DI -mAChE complex with the PAS-occluding short  loop
(yellow) of subunit A in the mAChE tetrameric assembly (1MAA),
according to all C[ ]atoms
of mAChE in the DI -mAChE complex and in the tetramer subunit C.
Those of the mAChE short loop
side chains that match the structural determinants of the DI
molecule are displayed as orange bonds. The mAChE molecular
surfaces buried at the Fas2 -mAChE complex interface (A) and at
the loop
-PAS interface (B) are shown in transparency.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2003,
22,
1-0)
copyright 2003.
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