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Stepwise activation of a metabotropic glutamate receptor

Author

Listed:
  • Kaavya Krishna Kumar

    (Stanford University School of Medicine)

  • Haoqing Wang

    (Stanford University School of Medicine
    Stanford University)

  • Chris Habrian

    (Stanford University School of Medicine)

  • Naomi R. Latorraca

    (University of California, Berkeley)

  • Jun Xu

    (Stanford University School of Medicine)

  • Evan S. O’Brien

    (Stanford University School of Medicine)

  • Chensong Zhang

    (SLAC National Accelerator Laboratory)

  • Elizabeth Montabana

    (Stanford University School of Medicine)

  • Antoine Koehl

    (Stanford University School of Medicine
    University of California, Berkeley)

  • Susan Marqusee

    (University of California, Berkeley
    University of California, Berkeley
    University of California, Berkeley)

  • Ehud Y. Isacoff

    (University of California, Berkeley
    University of California, Berkeley)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

Abstract

Metabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich domain to their 7-transmembrane domain1. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the extracellular ligand-binding domain to the G protein-coupling 7-transmembrane domain2. In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging, we reveal distinct receptor conformations upon allosteric modulator and G protein binding.

Suggested Citation

  • Kaavya Krishna Kumar & Haoqing Wang & Chris Habrian & Naomi R. Latorraca & Jun Xu & Evan S. O’Brien & Chensong Zhang & Elizabeth Montabana & Antoine Koehl & Susan Marqusee & Ehud Y. Isacoff & Brian K., 2024. "Stepwise activation of a metabotropic glutamate receptor," Nature, Nature, vol. 629(8013), pages 951-956, May.
    • Handle: RePEc:nat:nature:v:629:y:2024:i:8013:d:10.1038_s41586-024-07327-x
    DOI: 10.1038/s41586-024-07327-x
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    Cited by:

    1. Mingyu Li & Xiaobing Lan & Xinchao Shi & Chunhao Zhu & Xun Lu & Jun Pu & Shaoyong Lu & Jian Zhang, 2024. "Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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