Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2102-7. doi: 10.1073/pnas.1117275109. Epub 2012 Jan 20.
Resistance to the antibiotic fusidic acid (FA) in the human pathogen Staphylococcus aureus usually results from expression of FusB-type proteins (FusB or FusC). These proteins bind to elongation factor G (EF-G), the target of FA, and rescue translation from FA-mediated inhibition by an unknown mechanism. Here we show that the FusB family are two-domain metalloproteins, the C-terminal domain of which contains a four-cysteine zinc finger with a unique structural fold. This domain mediates a high-affinity interaction with the C-terminal domains of EF-G. By binding to EF-G on the ribosome, FusB-type proteins promote the dissociation of stalled ribosome⋅EF-G⋅GDP complexes that form in the presence of FA, thereby allowing the ribosomes to resume translation. Ribosome clearance by these proteins represents a highly unusual antibiotic resistance mechanism, which appears to be fine-tuned by the relative abundance of FusB-type protein, ribosomes, and EF-G.
金黄色葡萄球菌（Staphylococcus aureus）是一种人体病原体，其对抗生素夫西地酸（fusidic acid，FA）的耐药性通常是由于 FusB 型蛋白（FusB 或 FusC）的表达所致。这些蛋白与 EF-G（elongation factor G，FA 的靶标）结合，通过未知机制从 FA 介导的抑制中拯救翻译。在这里，我们表明 FusB 家族是具有两个结构域的金属蛋白酶，其 C 端结构域包含一个具有独特结构折叠的四半胱氨酸锌指。该结构域介导与 EF-G 的 C 端结构域的高亲和力相互作用。通过与核糖体上的 EF-G 结合，FusB 型蛋白促进 FA 存在时形成的核糖体⋅EF-G⋅GDP 复合物的解聚，从而使核糖体能够恢复翻译。这些蛋白通过核糖体清除来发挥作用，代表了一种非常不寻常的抗生素耐药机制，这种机制似乎通过 FusB 型蛋白、核糖体和 EF-G 的相对丰度进行精细调节。
