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Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go

Author

Listed:
  • Javier García-Nafría

    (MRC Laboratory of Molecular Biology)

  • Rony Nehmé

    (MRC Laboratory of Molecular Biology)

  • Patricia C. Edwards

    (MRC Laboratory of Molecular Biology)

  • Christopher G. Tate

    (MRC Laboratory of Molecular Biology)

Abstract

G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of Gs to four different GPCRs have been elucidated1–4, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT1B receptor (5-HT1BR) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β2-adrenoceptor (β2AR)3 or the adenosine A2A receptor (A2AR)1 in complex with Gs. In contrast to the complexes with Gs, the gap between the receptor and the Gβ-subunit in the Go–5-HT1BR complex precludes molecular contacts, and the interface between the Gα-subunit of Go and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the Go α-subunit. The molecular variations between the interfaces of Go and Gs in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.

Suggested Citation

  • Javier García-Nafría & Rony Nehmé & Patricia C. Edwards & Christopher G. Tate, 2018. "Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go," Nature, Nature, vol. 558(7711), pages 620-623, June.
  • Handle: RePEc:nat:nature:v:558:y:2018:i:7711:d:10.1038_s41586-018-0241-9
    DOI: 10.1038/s41586-018-0241-9
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    Cited by:

    1. Xuan Zhang & Guibing Liu & Ya-Ni Zhong & Ru Zhang & Chuan-Cheng Yang & Canyang Niu & Xuanyu Pu & Jingjing Sun & Tianyao Zhang & Lejin Yang & Chao Zhang & Xiu Li & Xinyuan Shen & Peng Xiao & Jin-Peng S, 2024. "Structural basis of ligand recognition and activation of the histamine receptor family," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Manbir Sandhu & Aaron Cho & Ning Ma & Elizaveta Mukhaleva & Yoon Namkung & Sangbae Lee & Soumadwip Ghosh & John H. Lee & David E. Gloriam & Stéphane A. Laporte & M. Madan Babu & Nagarajan Vaidehi, 2022. "Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. 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.
    6. Marin Matic & Pasquale Miglionico & Manae Tatsumi & Asuka Inoue & Francesco Raimondi, 2023. "GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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