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Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Author

Listed:
  • Yan Zhang

    (University of Michigan Medical School)

  • Bingfa Sun

    (ConfometRx)

  • Dan Feng

    (ConfometRx)

  • Hongli Hu

    (University of Michigan Medical School)

  • Matthew Chu

    (ConfometRx)

  • Qianhui Qu

    (University of Michigan Medical School)

  • Jeffrey T. Tarrasch

    (University of Michigan Medical School)

  • Shane Li

    (ConfometRx)

  • Tong Sun Kobilka

    (ConfometRx)

  • Brian K. Kobilka

    (ConfometRx
    Stanford University School of Medicine)

  • Georgios Skiniotis

    (University of Michigan Medical School
    Stanford University School of Medicine)

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.

Suggested Citation

  • Yan Zhang & Bingfa Sun & Dan Feng & Hongli Hu & Matthew Chu & Qianhui Qu & Jeffrey T. Tarrasch & Shane Li & Tong Sun Kobilka & Brian K. Kobilka & Georgios Skiniotis, 2017. "Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein," Nature, Nature, vol. 546(7657), pages 248-253, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7657:d:10.1038_nature22394
    DOI: 10.1038/nature22394
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    Cited by:

    1. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Xudong Wang & Chris Neale & Soo-Kyung Kim & William A. Goddard & Libin Ye, 2023. "Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Yong-Seok Kim & Jun-Hee Yeon & Woori Ko & Byung-Chang Suh, 2023. "Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Xueqian Peng & Linlin Yang & Zixuan Liu & Siyi Lou & Shiliu Mei & Meiling Li & Zhong Chen & Haitao Zhang, 2022. "Structural basis for recognition of antihistamine drug by human histamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Xinyan Zhu & Yu Qian & Xiaowan Li & Zhenmei Xu & Ruixue Xia & Na Wang & Jiale Liang & Han Yin & Anqi Zhang & Changyou Guo & Guangfu Wang & Yuanzheng He, 2022. "Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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