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PDBsum entry 2dfp
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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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Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level.
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Authors
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C.B.Millard,
G.Kryger,
A.Ordentlich,
H.M.Greenblatt,
M.Harel,
M.L.Raves,
Y.Segall,
D.Barak,
A.Shafferman,
I.Silman,
J.L.Sussman.
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Ref.
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Biochemistry, 1999,
38,
7032-7039.
[DOI no: ]
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PubMed id
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Abstract
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Organophosphorus acid anhydride (OP) nerve agents are potent inhibitors which
rapidly phosphonylate acetylcholinesterase (AChE) and then may undergo an
internal dealkylation reaction (called "aging") to produce an OP-enzyme
conjugate that cannot be reactivated. To understand the basis for irreversible
inhibition, we solved the structures of aged conjugates obtained by reaction of
Torpedo californica AChE (TcAChE) with diisopropylphosphorofluoridate (DFP),
O-isopropylmethylphosponofluoridate (sarin), or
O-pinacolylmethylphosphonofluoridate (soman) by X-ray crystallography to 2.3,
2.6, or 2.2 A resolution, respectively. The highest positive difference density
peak corresponded to the OP phosphorus and was located within covalent bonding
distance of the active-site serine (S200) in each structure. The OP-oxygen atoms
were within hydrogen-bonding distance of four potential donors from catalytic
subsites of the enzyme, suggesting that electrostatic forces significantly
stabilize the aged enzyme. The active sites of aged sarin- and soman-TcAChE were
essentially identical and provided structural models for the negatively charged,
tetrahedral intermediate that occurs during deacylation with the natural
substrate, acetylcholine. Phosphorylation with DFP caused an unexpected movement
in the main chain of a loop that includes residues F288 and F290 of the TcAChE
acyl pocket. This is the first major conformational change reported in the
active site of any AChE-ligand complex, and it offers a structural explanation
for the substrate selectivity of AChE.
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Secondary reference #1
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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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