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冷冻电镜实现蛋白结构的原子水平解析
2020-10-25 22:25

近日,德国马普研究所Holger Stark及其课题利用冷冻电镜实现蛋白结构的原子水平解析。2020年10月21日,《自然》杂志在线发表了这项成果。

研究人员使用最新开发冷冻电镜(cryo-EM)获得的1.25 A分辨率的去铁蛋白结构,该结构提供了前所未有的结构细节。这一去铁蛋白结构的3D信息含量几乎是当前世界纪录重建的两倍(1.54Å分辨率)。研究人员能够可视化蛋白质中的单个原子,查看氢原子的密度并成像单原子化学修饰。除了名义上提高分辨率外,研究人员还实现了cryo-EM密度图质量的显著提高,这与在基于结构的药物设计中使用cryo-EM高度相关。

据了解,单颗粒cryo-EM是解析生物大分子三维结构的有力方法。透射电子显微镜、检测器和自动程序的技术发展,加上用户友好的图像处理软件和不断增长的计算能力,使cryo-EM在过去十年中成为成功且不断扩展的技术。在高于4Å的分辨率下,开始可以建立原子模型,但是要直接可视化蛋白质结构中的真实原子位置,则需要更高的分辨率(优于1.5Å),而到目前为止,cryo-EM尚无法实现。原子位置的直接可视化对于理解蛋白质催化的化学反应的机理以及研究药物如何结合和干扰蛋白质的功能至关重要。

附:英文原文

Title: Atomic-resolution protein structure determination by cryo-EM

Author: Ka Man Yip, Niels Fischer, Elham Paknia, Ashwin Chari, Holger Stark

Issue&Volume: 2020-10-21

Abstract: Single-particle electron cryo-microscopy (cryo-EM) is a powerful method for solving the three-dimensional structures of biological macromolecules. The technological development of transmission electron microscopes, detectors and automated procedures in combination with user-friendly image processing software and ever-increasing computational power have made cryo-EM a successful and expanding technology over the past decade1. At resolutions better than 4 , atomic model building starts to become possible, but the direct visualization of true atomic positions in protein structure determination requires much higher (better than 1.5 ) resolution, which so far has not been attained by cryo-EM. The direct visualization of atom positions is essential for understanding the mechanisms of protein-catalysed chemical reactions, and for studying how drugs bind to and interfere with the function of proteins2. Here we report a 1.25 -resolution structure of apoferritin obtained by cryo-EM with a newly developed electron microscope that provides, to our knowledge, unprecedented structural detail. Our apoferritin structure has almost twice the 3D information content of the current world record reconstruction (at 1.54 resolution3). We can visualize individual atoms in a protein, see density for hydrogen atoms and image single-atom chemical modifications. Beyond the nominal improvement in resolution, we also achieve a substantial improvement in the quality of the cryo-EM density map, which is highly relevant for using cryo-EM in structure-based drug design.

DOI: 10.1038/s41586-020-2833-4

Source: https://www.nature.com/articles/s41586-020-2833-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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