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Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5

Author

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  • Mingyu Li

    (Shanghai Jiao Tong University School of Medicine
    Ningxia Medical University)

  • Xiaobing Lan

    (Ningxia Medical University)

  • Xinchao Shi

    (Shanghai Jiao Tong University School of Medicine)

  • Chunhao Zhu

    (Ningxia Medical University)

  • Xun Lu

    (Shanghai Jiao Tong University School of Medicine)

  • Jun Pu

    (Shanghai Jiao Tong University School of Medicine)

  • Shaoyong Lu

    (Shanghai Jiao Tong University School of Medicine
    Ningxia Medical University)

  • Jian Zhang

    (Shanghai Jiao Tong University School of Medicine
    Ningxia Medical University)

Abstract

Two-thirds of signaling hormones and one-third of approved drugs exert their effects by binding and modulating the G protein-coupled receptors (GPCRs) activation. While the activation mechanism for monomeric GPCRs has been well-established, little is known about GPCRs in dimeric form. Here, by combining transition pathway generation, extensive atomistic simulation-based Markov state models, and experimental signaling assays, we reveal an asymmetric, stepwise millisecond allosteric activation mechanism for the metabotropic glutamate receptor subtype 5 receptor (mGlu5), an obligate dimeric class C GPCR. The dynamic picture is presented that agonist binding induces dimeric ectodomains compaction, amplified by the precise association of the cysteine-rich domains, ultimately loosely bringing the intracellular 7-transmembrane (7TM) domains into proximity and establishing an asymmetric TM6-TM6 interface. The active inter-domain interface enhances their intra-domain flexibility, triggering the activation of micro-switches crucial for downstream signal transduction. Furthermore, we show that the positive allosteric modulator stabilizes both the active inter-domain 7TM interface and an open, extended intra-domain ICL2 conformation. This stabilization leads to the formation of a pseudo-cavity composed of the ICL2, ICL3, TM3, and C-terminus, which facilitates G protein coordination. Our strategy may be generalizable for characterizing millisecond events in other allosteric systems.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51999-y
    DOI: 10.1038/s41467-024-51999-y
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