Departments of Chemistry, Yale University, Howard Hughes Medical Institute, New Haven, CT 06511, USA.
Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17158-63. doi: 10.1073/pnas.1008685107. Epub 2010 Sep 27.
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.
抗生素耐药病原体的日益流行，加强了对结构的抗生素核糖体复合物，是准确的，足以使合理设计的新型核糖体靶向治疗。结构的许多抗生素复杂的既archaeal和真核核糖体已被确定，但几个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的变化，或从实验的问题。我们的结构氯霉素在复杂的 70S 核糖体从 Thermus thermophilus 表明一个模型氯霉素绑定到大亚基的细菌核糖体，是从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在复杂的细菌核糖体是从那些确定的复合物与 50S 亚基的 Haloarcula marismortui，但有很大的不同，从模型已经公布了 50S 亚基复合物的真细菌 Deinococcus radiodurans。我们的结构的抗生素telithromycin 绑定到 T. thermophilus 核糖体揭示了内酯环与构象类似于观察到的在 H. marismortui 和 D. radiodurans 复合物。然而，烷基芳基部分是不同的取向在所有三个生物体，和接触观察与 T. thermophilus 核糖体是一致的生化研究进行的大肠杆菌核糖体。因此，我们的研究结果支持一种模式的大环内酯类结合，在很大程度上是保守的跨物种，表明质量和解释电子密度，而不是物种特异性，可能是负责许多差异之间的模型。
