1] Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany [2] Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Institute for Biochemistry and Molecular Biology, ZMBZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Stefan-Meier-Strasse 17, 79104 Freiburg, Germany.
Nat Commun. 2014 Jun 4;5:4029. doi: 10.1038/ncomms5029.
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.
阿托伐醌是一种取代的羟萘醌，是一种有效的抗疟药物，通过抑制寄生虫的线粒体细胞色素 bc1 复合物（细胞色素 bc1）发挥作用。细胞色素 bc1 中的突变导致阿托伐醌耐药。在这里，我们描述了酿酒酵母线粒体细胞色素 bc1 的 X 射线结构，阿托伐醌结合在催化 Qo 位，分辨率为 3.0-Å。细胞色素 bc1 中的 Rieske 蛋白中的氢键将药物的离子化羟基捕获。细胞色素 b 高度保守残基的侧链与萘醌基团建立了多个非极性相互作用，而不太保守的残基与阿托伐醌的环己基-氯苯基尾部接触。我们的结构分析揭示了阿托伐醌广泛的靶谱、物种特异性疗效和获得性耐药的分子基础，并可能有助于药物开发以控制耐药寄生虫的传播。
