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PDBsum entry 4pd4
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Oxidoreductase/inhibitor
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PDB id
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4pd4
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Contents |
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431 a.a.
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352 a.a.
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385 a.a.
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248 a.a.
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185 a.a.
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74 a.a.
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126 a.a.
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93 a.a.
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57 a.a.
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127 a.a.
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107 a.a.
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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 analysis of atovaquone-Inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action.
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Authors
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D.Birth,
W.C.Kao,
C.Hunte.
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Ref.
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Nat Commun, 2014,
5,
4029.
[DOI no: ]
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PubMed id
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Abstract
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Atovaquone, a substituted hydroxynaphthoquinone, is a potent antimalarial drug
that acts by inhibiting the parasite's mitochondrial cytochrome bc1 complex (cyt
bc1). Mutations in cyt bc1 confer atovaquone resistance. Here we describe the
X-ray structure of mitochondrial cyt bc1 from Saccharomyces cerevisiae with
atovaquone bound in the catalytic Qo site, at 3.0-Å resolution. A polarized
H-bond to His181 of the Rieske protein in cyt bc1 traps the ionized hydroxyl
group of the drug. Side chains of highly conserved cytochrome b residues
establish multiple non-polar interactions with the napththoquinone group,
whereas less-conserved residues are in contact with atovaquone's
cyclohexyl-chlorophenyl tail. Our structural analysis reveals the molecular
basis of atovaquone's broad target spectrum, species-specific efficacies and
acquired resistances, and may aid drug development to control the spread of
resistant parasites.
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