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Retrieving functional pathways of biomolecules from single-particle snapshots.
Nature Communications ( IF 16.6 ) Pub Date : 2020-09-18 , DOI: 10.1038/s41467-020-18403-x
Ali Dashti 1 , Ghoncheh Mashayekhi 1 , Mrinal Shekhar 2, 3 , Danya Ben Hail 4 , Salah Salah 4, 5, 6 , Peter Schwander 1 , Amedee des Georges 4, 5, 6 , Abhishek Singharoy 3 , Joachim Frank 7, 8 , Abbas Ourmazd 1
Affiliation  

A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations.



中文翻译:

从单粒子快照中检索生物分子的功能通路。

对结构生物学产生浓厚兴趣的一个主要原因是结构知识可以阐明生物体中的大分子功能。持续的努力产生了令人印象深刻的用于确定静态结构的工具库。但在生理条件下,大分子会经历连续的构象变化,其中一部分在功能上很重要。捕捉功能潜在的连续构象变化的技术对于进一步取得进展至关重要。在这里,我们展示了生物功能的化学详细构象电影,从兰尼碱受体 1 型 (RyR1) 的实验性单粒子低温电子显微镜 (cryo-EM) 快照中提取的数据分析,这是一种钙激活的钙通道参与配体的结合。在构象活性结构域的性质、构象运动的顺序和程度以及变构信号在域内和域之间的转导方式方面,功能运动与从静态结构推断的运动有很大不同。我们的方法强调了结合实验、高级数据分析和分子模拟的重要性。

更新日期:2020-09-20
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