小柯机器人

结构生物学揭示A类和B类G蛋白激活的差异
2020-07-31 15:36

美国斯坦福大学医学院Brian K. Kobilka、Georgios Skiniotis和丹麦Zealand Pharma A/S公司Jesper Mosolff Mathiesen小组合作取得一项新成果。他们利用结构生物学揭示了鸟嘌呤核苷酸结合蛋白(G蛋白)偶联受体(GPCR) A类和B类G蛋白激活的差异。2020年7月31日,《科学》发表了这一成果。

为了研究GPCR不同家族结构差异对功能的影响,研究人员比较了胰高血糖素受体(GCGR;B类)和β2肾上腺素素受体(β2AR;A类)的结构和功能。通过冷冻电镜研究人员解析了分辨率为3.1埃的GCGR-Gs复合物结构。此结构显示TM6中存在明显中断。

鸟苷三磷酸(GTP)转换、鸟苷二磷酸释放、GTP结合和G蛋白解离研究表明,与β2AR相比,GCGR激活G蛋白的速度要慢得多。荧光和电子-电子双共振研究表明,这种差异是由于单一激动剂无法诱导跨膜区段6(TM6)的细胞质末端产生可检测的向外运动。

据介绍,B类异三聚体鸟嘌呤核苷酸结合蛋白偶联受体在碳水化合物代谢中起重要作用。B类GPCR-Gs蛋白复合物的最新结构揭示了在A类GPCR中未观察到的TM6 α-螺旋的破坏。

附:英文原文

Title: Structural insights into differences in G protein activation by family A and family B GPCRs

Author: Daniel Hilger, Kaavya Krishna Kumar, Hongli Hu, Mie Fabricius Pedersen, Evan S. O’Brien, Lise Giehm, Christine Jennings, Gzde Eskici, Asuka Inoue, Michael Lerch, Jesper Mosolff Mathiesen, Georgios Skiniotis, Brian K. Kobilka

Issue&Volume: 2020/07/31

Abstract: Family B heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-Gs protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β2 adrenergic receptor (β2AR; family A). We determined the structure of the GCGR-Gs complex by means of cryo–electron microscopy at 3.1-angstrom resolution. This structure shows the distinct break in TM6. Guanosine triphosphate (GTP) turnover, guanosine diphosphate release, GTP binding, and G protein dissociation studies revealed much slower rates for G protein activation by the GCGR compared with the β2AR. Fluorescence and double electron-electron resonance studies suggest that this difference is due to the inability of agonist alone to induce a detectable outward movement of the cytoplasmic end of TM6.

DOI: 10.1126/science.aba3373

Source: https://science.sciencemag.org/content/369/6503/eaba3373

Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037
官方网址:https://www.sciencemag.org/
投稿链接:https://cts.sciencemag.org/scc/#/login

本期文章:《科学》:Volume 369 Issue 6503

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