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PDBsum entry 4d6t
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Electron transport
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PDB id
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4d6t
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Contents |
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444 a.a.
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422 a.a.
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374 a.a.
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240 a.a.
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73 a.a.
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98 a.a.
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80 a.a.
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65 a.a.
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21 a.a.
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58 a.a.
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196 a.a.
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74 a.a.
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17 a.a.
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59 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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Antimalarial 4(1h)-Pyridones bind to the qi site of cytochrome bc1.
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Authors
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M.J.Capper,
P.M.O'Neill,
N.Fisher,
R.W.Strange,
D.Moss,
S.A.Ward,
N.G.Berry,
A.S.Lawrenson,
S.S.Hasnain,
G.A.Biagini,
S.V.Antonyuk.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
755-760.
[DOI no: ]
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PubMed id
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Abstract
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Cytochrome bc1 is a proven drug target in the prevention and treatment of
malaria. The rise in drug-resistant strains of Plasmodium falciparum, the
organism responsible for malaria, has generated a global effort in designing new
classes of drugs. Much of the design/redesign work on overcoming this resistance
has been focused on compounds that are presumed to bind the Qo site (one of two
potential binding sites within cytochrome bc1) using the known crystal structure
of this large membrane-bound macromolecular complex via in silico modeling.
Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of
inhibitors, GSK932121 and GW844520, that have been shown to be potent
antimalarial agents in vivo, revealed that these inhibitors do not bind at the
Qo site but bind at the Qi site. The discovery that these compounds bind at the
Qi site may provide a molecular explanation for the cardiotoxicity and eventual
failure of GSK932121 in phase-1 clinical trial and highlight the need for direct
experimental observation of a compound bound to a target site before chemical
optimization and development for clinical trials. The binding of the
4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class
to overcome parasite Qo-based atovaquone resistance and provides critical
structural information for future design of new selective compounds with
improved safety profiles.
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