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Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

Author

Listed:
  • Yi-Lynn Liang

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Maryam Khoshouei

    (Max Planck Institute of Biochemistry
    Novartis Institutes for Biomedical Research, Novartis Pharma)

  • Giuseppe Deganutti

    (School of Biological Sciences, University of Essex)

  • Alisa Glukhova

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Cassandra Koole

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Thomas S. Peat

    (CSIRO Biomedical Manufacturing)

  • Mazdak Radjainia

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Thermo Fisher Scientific)

  • Jürgen M. Plitzko

    (Max Planck Institute of Biochemistry)

  • Wolfgang Baumeister

    (Max Planck Institute of Biochemistry)

  • Laurence J. Miller

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Mayo Clinic)

  • Deborah L. Hay

    (University of Auckland
    University of Auckland)

  • Arthur Christopoulos

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Christopher A. Reynolds

    (School of Biological Sciences, University of Essex)

  • Denise Wootten

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Fudan University)

  • Patrick M. Sexton

    (Monash Institute of Pharmaceutical Sciences, Monash University
    Fudan University)

Abstract

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the Gs-protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.

Suggested Citation

  • Yi-Lynn Liang & Maryam Khoshouei & Giuseppe Deganutti & Alisa Glukhova & Cassandra Koole & Thomas S. Peat & Mazdak Radjainia & Jürgen M. Plitzko & Wolfgang Baumeister & Laurence J. Miller & Deborah L., 2018. "Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor," Nature, Nature, vol. 561(7724), pages 492-497, September.
    • Handle: RePEc:nat:nature:v:561:y:2018:i:7724:d:10.1038_s41586-018-0535-y
    DOI: 10.1038/s41586-018-0535-y
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    Citations

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    Cited by:

    1. Kaleeckal G. Harikumar & Sarah J. Piper & Arthur Christopoulos & Denise Wootten & Patrick M. Sexton & Laurence J. Miller, 2024. "Impact of secretin receptor homo-dimerization on natural ligand binding," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Yingna Xu & Wenbo Feng & Qingtong Zhou & Anyi Liang & Jie Li & Antao Dai & Fenghui Zhao & Jiahui Yan & Chuan-Wei Chen & Hao Li & Li-Hua Zhao & Tian Xia & Yi Jiang & H. Eric Xu & Dehua Yang & Ming-Wei , 2022. "A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. 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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