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

Mingyu Li, Xiaobing Lan, Xinchao Shi, Chunhao Zhu, Xun Lu, Jun Pu, Shaoyong Lu () and Jian Zhang ()
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Mingyu Li: Shanghai Jiao Tong University School of Medicine
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
Jian Zhang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51999-y

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