文章：

高分辨率可视化的人类细胞翻译动力学揭示抗癌药物作用机制

Translation dynamics in human cells visualized at high resolution reveal cancer drug action

原文发布日期：2023-06-06

DOI: 10.1126/science.adh1411

类型: Research Article

开放获取: 否

文章简介：

Editor’s summary

Ribosomes are molecular machines that translate genetic information into proteins. Their active site is the target of many small molecules, including several antibiotics and the anticancer drug homoharringtonine. Although structural biologists have studied how small molecules interfere with ribosome function in the test tube, Xing et al. now reveal structures of translating ribosomes within human cells using cryo–electron tomography. The authors visualized translation intermediates at high resolution and elucidated in detail how homoharringtonine acts on ribosomes. This work marks a technical advance in solving high-resolution structures from inside human cells and adds to our understanding of this drug’s effect on cells. —SMH

Abstract

Ribosomes catalyze protein synthesis by cycling through various functional states. These states have been extensively characterized in vitro, but their distribution in actively translating human cells remains elusive. We used a cryo–electron tomography-based approach and resolved ribosome structures inside human cells with high resolution. These structures revealed the distribution of functional states of the elongation cycle, a Z transfer RNA binding site, and the dynamics of ribosome expansion segments. Ribosome structures from cells treated with Homoharringtonine, a drug used against chronic myeloid leukemia, revealed how translation dynamics were altered in situ and resolve the small molecules within the active site of the ribosome. Thus, structural dynamics and drug effects can be assessed at high resolution within human cells.

简介翻译： 

编者概要

核糖体是将遗传信息翻译成蛋白质的分子机器。其活性位点是许多小分子的作用靶点，包括多种抗生素以及抗癌药物高三尖杉酯碱。尽管结构生物学家已在试管中研究了小分子如何干扰核糖体功能，但Xing等人如今利用冷冻电子断层扫描技术揭示了人体细胞内翻译过程中核糖体的结构。作者以高分辨率可视化了翻译中间体，并详细阐明了高三尖杉酯碱如何作用于核糖体。这项工作标志着在解决人体细胞内高分辨率结构方面的技术进步，并增进了我们对该药物在细胞中作用的理解。—SMH

摘要

核糖体通过循环经历多种功能状态来催化蛋白质合成。这些状态已在体外得到广泛表征，但它们在活跃翻译的人体细胞中的分布仍不明确。我们采用基于冷冻电子断层扫描的方法，以高分辨率解析了人体细胞内的核糖体结构。这些结构揭示了延伸循环的功能状态分布、一个Z转移RNA结合位点以及核糖体扩张段的动态变化。从经高三尖杉酯碱（一种用于治疗慢性粒细胞白血病的药物）处理的细胞中获得的核糖体结构，揭示了翻译动态在原位如何被改变，并解析了核糖体活性位点内的小分子。因此，我们可以在人体细胞内以高分辨率评估结构动态与药物效应。

原文链接：

Translation dynamics in human cells visualized at high resolution reveal cancer drug action