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质谱捕捉到G-蛋白偶联受体的偏导信号和变构调制
作者:小柯机器人 发布时间:2022/11/12 14:12:51

英国牛津大学Robinson Carol V.团队报道质谱捕捉到G-蛋白偶联受体的偏导信号和变构调制。相关研究成果发表在2022年11月10日出版的国际知名学术期刊《自然—化学》。

G蛋白偶联受体通过同源G蛋白发出信号。尽管这些受体具有广泛的重要性,但它们对G蛋白选择性的调节机制尚未完全了解。

该文中,研究人员提出了一种基于天然质谱的方法来测定β1-肾上腺素能受体对各种配体的偏倚信号和变构调节。通过同时捕捉配体结合和受体偶联到不同G蛋白的作用,研究人员通过14种配体的系统变化,探讨了与受体特异性相互作用的相对重要性,包括异丙肾上腺素衍生物、完全和部分激动剂以及拮抗剂。

研究人员观察到在异丙肾上腺素的存在下,细胞内环3的动力学增强,异丙肾上腺素能够作为一种偏压激动剂。研究还表明,内源性锌离子增强了受体-Gs复合物中的结合,并在受体-Gs复合体的TM5/TM6细胞内界面处提出了锌离子结合热点。进一步的研究提出了一种机制,其中锌离子促进中间络合物向稳定态的结构转变。

附:英文原文

Title: Mass spectrometry captures biased signalling and allosteric modulation of a G-protein-coupled receptor

Author: Yen, Hsin-Yung, Liko, Idlir, Song, Wanling, Kapoor, Parth, Almeida, Fernando, Toporowska, Joanna, Gherbi, Karolina, Hopper, Jonathan T. S., Charlton, Steven J., Politis, Argyris, Sansom, Mark S. P., Jazayeri, Ali, Robinson, Carol V.

Issue&Volume: 2022-11-10

Abstract: G-protein-coupled receptors signal through cognate G proteins. Despite the widespread importance of these receptors, their regulatory mechanisms for G-protein selectivity are not fully understood. Here we present a native mass spectrometry-based approach to interrogate both biased signalling and allosteric modulation of the β1-adrenergic receptor in response to various ligands. By simultaneously capturing the effects of ligand binding and receptor coupling to different G proteins, we probed the relative importance of specific interactions with the receptor through systematic changes in 14 ligands, including isoprenaline derivatives, full and partial agonists, and antagonists. We observed enhanced dynamics of the intracellular loop 3 in the presence of isoprenaline, which is capable of acting as a biased agonist. We also show here that endogenous zinc ions augment the binding in receptor–Gs complexes and propose a zinc ion-binding hotspot at the TM5/TM6 intracellular interface of the receptor–Gs complex. Further interrogation led us to propose a mechanism in which zinc ions facilitate a structural transition of the intermediate complex towards the stable state.

DOI: 10.1038/s41557-022-01041-9

Source: https://www.nature.com/articles/s41557-022-01041-9

期刊信息

Nature Chemistry:《自然—化学》,创刊于2009年。隶属于施普林格·自然出版集团,最新IF:21.687
官方网址:https://www.nature.com/nchem/
投稿链接:https://mts-nchem.nature.com/cgi-bin/main.plex