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PDBsum entry 5e2i
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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 impact of crystallization conditions on structure-Based drug design: a case study on the methylene blue/acetylcholinesterase complex.
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Authors
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O.Dym,
W.Song,
C.Felder,
E.Roth,
V.Shnyrov,
Y.Ashani,
Y.Xu,
R.P.Joosten,
L.Weiner,
J.L.Sussman,
I.Silman.
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Ref.
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Protein Sci, 2016,
25,
1096-1114.
[DOI no: ]
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PubMed id
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Abstract
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Structure-based drug design utilizes apoprotein or complex structures retrieved
from the PDB. >57% of crystallographic PDB entries were obtained with
polyethylene glycols (PEGs) as precipitant and/or as cryoprotectant, but <6%
of these report presence of individual ethyleneglycol oligomers. We report a
case in which ethyleneglycol oligomers' presence in a crystal structure markedly
affected the bound ligand's position. Specifically, we compared the positions of
methylene blue and decamethonium in acetylcholinesterase complexes obtained
using isomorphous crystals precipitated with PEG200 or ammonium sulfate. The
ligands' positions within the active-site gorge in complexes obtained using
PEG200 are influenced by presence of ethyleneglycol oligomers in both cases
bound to W84 at the gorge's bottom, preventing interaction of the ligand's
proximal quaternary group with its indole. Consequently, both ligands are
∼3.0Å further up the gorge than in complexes obtained using crystals
precipitated with ammonium sulfate, in which the quaternary groups make direct
π-cation interactions with the indole. These findings have implications for
structure-based drug design, since data for ligand-protein complexes with
polyethylene glycol as precipitant may not reflect the ligand's position in its
absence, and could result in selecting incorrect drug discovery leads. Docking
methylene blue into the structure obtained with PEG200, but omitting the
ethyleneglycols, yields results agreeing poorly with the crystal structure;
excellent agreement is obtained if they are included. Many proteins display
features in which precipitants might lodge. It will be important to investigate
presence of precipitants in published crystal structures, and whether it has
resulted in misinterpreting electron density maps, adversely affecting drug
design.
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