結構生物學揭示A類和B類G蛋白激活的差異
作者:
小柯機器人發布時間:2020/7/31 15:36:36
美國史丹福大學醫學院Brian K. Kobilka、Georgios Skiniotis和丹麥Zealand Pharma A/S公司Jesper Mosolff Mathiesen小組合作取得一項新成果。他們利用結構生物學揭示了鳥嘌呤核苷酸結合蛋白(G蛋白)偶聯受體(GPCR) A類和B類G蛋白激活的差異。2020年7月31日,《科學》發表了這一成果。
為了研究GPCR不同家族結構差異對功能的影響,研究人員比較了胰高血糖素受體(GCGR;B類)和β2腎上腺素素受體(β2AR;A類)的結構和功能。通過冷凍電鏡研究人員解析了解析度為3.1埃的GCGR-Gs複合物結構。此結構顯示TM6中存在明顯中斷。
鳥苷三磷酸(GTP)轉換、鳥苷二磷酸釋放、GTP結合和G蛋白解離研究表明,與β2AR相比,GCGR激活G蛋白的速度要慢得多。螢光和電子-電子雙共振研究表明,這種差異是由於單一激動劑無法誘導跨膜區段6(TM6)的細胞質末端產生可檢測的向外運動。
據介紹,B類異三聚體鳥嘌呤核苷酸結合蛋白偶聯受體在碳水化合物代謝中起重要作用。B類GPCR-Gs蛋白複合物的最新結構揭示了在A類GPCR中未觀察到的TM6 α-螺旋的破壞。
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:《科學》,創刊於1880年。隸屬於美國科學促進會,最新IF:41.037