Drug sensing by the ribosome induces translational arrest via active site perturbation.
Drug sensing by the ribosome induces translational arrest via active site perturbation.
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DOI：
10.1016/j.molcel.2014.09.014
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发表时间：
2014-11-06
期刊：
影响因子：
16
通讯作者：
Wilson DN
中科院分区：
文献类型：
--
作者：
Arenz S;Meydan S;Starosta AL;Berninghausen O;Beckmann R;Vázquez-Laslop N;Wilson DN
在蛋白质合成过程中，核糖体通道内新生多肽链可以顺式作用，诱导核糖体停滞，调控下游基因的表达。金黄色葡萄球菌ErmCL先导肽在临床上重要的大环内酯类抗生素（如红霉素）存在时诱导阻滞，导致下游大环内酯耐药甲基转移酶ErmC的诱导。在这里，我们展示了红霉素依赖的ermcl停滞核糖体的低温电镜（EM）结构，分辨率为3.9 Å。该结构揭示了ErmCL新生链如何直接感知隧道结合药物的存在，从而诱导核糖体肽基转移酶中心（PTC）的变构构象重排。ermcl诱导的PTC的扰动阻止了a位点上氨基酰基trna的稳定结合和调节，从而抑制了肽键的形成和翻译停滞。
During protein synthesis, nascent polypeptide chains within the ribosomal tunnel can act in cis to induce ribosome stalling and regulate expression of downstream genes. The Staphylococcus aureus ErmCL leader peptide induces stalling in the presence of clinically important macrolide antibiotics, such as erythromycin, leading to the induction of the downstream macrolide resistance methyltransferase ErmC. Here, we present a cryo-electron microscopy (EM) structure of the erythromycin-dependent ErmCL-stalled ribosome at 3.9 Å resolution. The structure reveals how the ErmCL nascent chain directly senses the presence of the tunnel-bound drug and thereby induces allosteric conformational rearrangements at the peptidyltransferase center (PTC) of the ribosome. ErmCL-induced perturbations of the PTC prevent stable binding and accommodation of the aminoacyl-tRNA at the A-site leading to inhibition of peptide bond formation and translation arrest.