Revisiting the structures of several antibiotics bound to the bacterial ribosome
Revisiting the structures of several antibiotics bound to the bacterial ribosome
复制标题
DOI：
10.1073/pnas.1008685107
复制
发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Steitz, Thomas A.
中科院分区：
文献类型：
--
作者：
Bulkley, David;Innis, C. Axel;Steitz, Thomas A.
越来越多的耐药病原体的流行加强了对足够精确的耐药-核糖体复合物的结构的需要，以使得能够合理设计新的核糖体靶向治疗剂。许多抗生素与古细菌和真细菌核糖体复合的结构已经确定，但这些模型之间的差异提出了一个问题，即这些差异是否来自物种特异性变异或实验问题。我们的氯霉素与嗜热栖热菌的70 S核糖体复合的结构表明氯霉素与细菌核糖体的大亚基结合的模型与流行的模型完全不同。此外，我们的结构的大环内酯类抗生素红霉素和阿奇霉素与细菌核糖体的复合物是不可区分的，从那些确定的复合物与50 S亚基的海洋盐球藻，但显着不同的模型，已公布的50 S亚基复合物的耐辐射真杆菌。我们的抗生素泰利霉素的结构结合到T。嗜热菌核糖体显示了一个内酯环，其构象与在H. marismortui和D.抗辐射铀配合物。然而，烷基-芳基部分在所有三种生物体中的取向不同，并且观察到与T.嗜热菌核糖体的生物化学研究与大肠杆菌核糖体的生物化学研究一致。因此，我们的研究结果支持大环内酯结合的模式，这在很大程度上是保守的物种，这表明电子密度的质量和解释，而不是物种特异性，可能是负责模型之间的许多差异。
The increasing prevalence of antibiotic-resistant pathogens reinforces the need for structures of antibiotic-ribosome complexes that are accurate enough to enable the rational design of novel ribosome-targeting therapeutics. Structures of many antibiotics in complex with both archaeal and eubacterial ribosomes have been determined, yet discrepancies between several of these models have raised the question of whether these differences arise from species-specific variations or from experimental problems. Our structure of chloramphenicol in complex with the 70S ribosome from Thermus thermophilus suggests a model for chloramphenicol bound to the large subunit of the bacterial ribosome that is radically different from the prevailing model. Further, our structures of the macrolide antibiotics erythromycin and azithromycin in complex with a bacterial ribosome are indistinguishable from those determined of complexes with the 50S subunit of Haloarcula marismortui, but differ significantly from the models that have been published for 50S subunit complexes of the eubacterium Deinococcus radiodurans. Our structure of the antibiotic telithromycin bound to the T. thermophilus ribosome reveals a lactone ring with a conformation similar to that observed in the H. marismortui and D. radiodurans complexes. However, the alkyl-aryl moiety is oriented differently in all three organisms, and the contacts observed with the T. thermophilus ribosome are consistent with biochemical studies performed on the Escherichia coli ribosome. Thus, our results support a mode of macrolide binding that is largely conserved across species, suggesting that the quality and interpretation of electron density, rather than species specificity, may be responsible for many of the discrepancies between the models.