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PDBsum entry 1ea5
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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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X-Ray structures of torpedo californica acetylcholinesterase complexed with (+)-Huperzine a and (-)-Huperzine b: structural evidence for an active site rearrangement.
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Authors
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H.Dvir,
H.L.Jiang,
D.M.Wong,
M.Harel,
M.Chetrit,
X.C.He,
G.Y.Jin,
G.L.Yu,
X.C.Tang,
I.Silman,
D.L.Bai,
J.L.Sussman.
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Ref.
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Biochemistry, 2002,
41,
10810-10818.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Kinetic and structural data are presented on the interaction with Torpedo
californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic
enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural
homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the
enzyme with dissociation constants of 4.30 and 0.33 microM, respectively,
compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the
complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to
2.1 and 2.35 A resolution, respectively, and compared to the previously
determined structure of the (-)-huperzine A complex. All three interact with the
"anionic" subsite of the active site, primarily through pi-pi stacking and
through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their
alpha-pyridone moieties are responsible for their key interactions with the
active site via hydrogen bonding, and possibly via C-H.pi interactions, all
three maintain similar positions and orientations with respect to it. The
carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117,
thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide
flip. As a consequence, the position of the main chain nitrogen of Gly118 in the
"oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117.
Furthermore, the flipped conformation is stabilized by hydrogen bonding of
Gly117O to Gly119N and Ala201N, the other two functional elements of the
three-pronged "oxyanion hole" characteristic of cholinesterases. All three
inhibitors thus would be expected to abolish hydrolysis of all ester substrates,
whether charged or neutral.
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Secondary reference #1
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Title
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Residues in torpedo californica acetylcholinesterase necessary for processing to a glycosyl phosphatidylinositol-Anchored form.
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Authors
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G.Bucht,
K.Hjalmarsson.
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Ref.
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Biochim Biophys Acta, 1996,
1292,
223-232.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-Ray crystallography.
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Authors
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P.H.Axelsen,
M.Harel,
I.Silman,
J.L.Sussman.
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Ref.
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Protein Sci, 1994,
3,
188-197.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Quaternary ligand binding to aromatic residues in the active-Site gorge of acetylcholinesterase.
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Authors
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M.Harel,
I.Schalk,
L.Ehret-Sabatier,
F.Bouet,
M.Goeldner,
C.Hirth,
P.H.Axelsen,
I.Silman,
J.L.Sussman.
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Ref.
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Proc Natl Acad Sci U S A, 1993,
90,
9031-9035.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Atomic structure of acetylcholinesterase from torpedo californica: a prototypic acetylcholine-Binding protein.
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Authors
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J.L.Sussman,
M.Harel,
F.Frolow,
C.Oefner,
A.Goldman,
L.Toker,
I.Silman.
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Ref.
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Science, 1991,
253,
872-879.
[DOI no: ]
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PubMed id
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Secondary reference #5
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Title
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Purification and crystallization of a dimeric form of acetylcholinesterase from torpedo californica subsequent to solubilization with phosphatidylinositol-Specific phospholipase c.
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Authors
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J.L.Sussman,
M.Harel,
F.Frolow,
L.Varon,
L.Toker,
A.H.Futerman,
I.Silman.
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Ref.
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J Mol Biol, 1988,
203,
821-823.
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PubMed id
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Secondary reference #6
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Title
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Primary structure of torpedo californica acetylcholinesterase deduced from its cdna sequence.
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Authors
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M.Schumacher,
S.Camp,
Y.Maulet,
M.Newton,
K.Macphee-Quigley,
S.S.Taylor,
T.Friedmann,
P.Taylor.
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Ref.
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Nature, 1986,
319,
407-409.
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PubMed id
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