A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase
A Crystal Structure of the Bifunctional Antibiotic Simocyclinone D8, Bound to DNA Gyrase
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DOI：
10.1126/science.1179123
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发表时间：
2009-12-04
期刊：
影响因子：
56.9
通讯作者：
Maxwell, Anthony
中科院分区：
文献类型：
--
作者：
Edwards, Marcus J.;Flatman, Ruth H.;Maxwell, Anthony
西莫环素是双功能抗生素，通过阻止 DNA 与细菌 DNA 旋转酶结合来抑制该酶。我们报告了大肠杆菌旋转酶 A 亚基的 N 端结构域和西莫环酮 D8 之间形成的复合物的晶体结构，揭示了两个分别容纳抗生素的氨基香豆素和聚酮化合物部分的结合袋。这些位点接近但不同于喹诺酮结合位点，这与我们的观察结果一致，即该区域的几个突变赋予了对两种药物的抗性。生化研究表明，与母体化合物相比，西莫环酮 D8 的各个部分是相对较弱的旋转酶抑制剂，但它们的组合产生了更有效的抑制剂。我们的结果应该有助于设计针对这些未利用的结合袋的药物分子。
Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.