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首页> 外文期刊>Biochemistry >Mass Spectrometry Reveals That the Antibiotic Simocyclinone D8 Binds to DNA Gyrase in a 'Bent-Over' Conformation: Evidence of Positive Cooperativity in Binding
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Mass Spectrometry Reveals That the Antibiotic Simocyclinone D8 Binds to DNA Gyrase in a 'Bent-Over' Conformation: Evidence of Positive Cooperativity in Binding

机译：质谱揭示了抗生素Simocyclinone D8以“弯曲”构型与DNA促旋酶结合：结合中有正合作性的证据

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摘要

DNA topoisomerases are enzymes that control DNA topology and are vital targets for antimicrobial and anticancer drugs. Here we present a mass spectrometry study of complexes formed between the A subunit of the topoisomerase DNA gyrase and the bifunctional inhibitor simocyclinone D8 (SD8), an antibiotic isolated from Streptomyces. These studies show that, in an alternative mode of interaction to that found by X-ray crystallography, each subunit binds a single bifunctional inhibitor with separate binding pockets for the two ends of SD8. The gyrase subunits form constitutive dimers, and fractional occupancies of inhibitor-bound states show that there is strong allosteric cooperativity in the binding of two bifunctional ligands to the dimer. We show that the mass spectrometry data can be fitted to a general model of cooperative binding via an extension of the tight-binding approach, providing a rigorous determination of the dissociation constants and degree of cooperativity. This general approach will be applicable to other systems with multiple binding sites and highlights mass spectrometrys role as a powerful emerging tool for unraveling the complexities of biomolecular interactions.
机译：DNA拓扑异构酶是控制DNA拓扑结构的酶，并且是抗微生物和抗癌药物的重要靶标。在这里，我们对拓扑异构酶DNA回旋酶的A亚基与双功能抑制剂simocyclinone D8（SD8）（一种从链霉菌中分离出的抗生素）之间形成的复合物进行了质谱研究。这些研究表明，在通过X射线晶体学发现的相互作用的一种替代模式中，每个亚基结合一个双功能抑制剂，并具有单独的SD8两端的结合袋。促旋酶亚基形成组成性二聚体，并且抑制剂结合状态的部分占有率表明在两个双功能配体与二聚体的结合中具有很强的变构协同作用。我们表明，质谱数据可以通过紧密结合方法的扩展适用于合作结合的一般模型，从而提供对解离常数和协同程度的严格确定。这种通用方法将适用于具有多个结合位点的其他系统，并着重说明了质谱仪作为一种强大的新兴工具来阐明生物分子相互作用的复杂性的作用。

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