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- Title
Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5.
- Authors
Li, Mingyu; Lan, Xiaobing; Shi, Xinchao; Zhu, Chunhao; Lu, Xun; Pu, Jun; Lu, Shaoyong; Zhang, Jian
- 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. Activation mechanism of GPCRs in dimeric form remains enigmatic. Here, the authors present a dynamic characterization of mGlu5, an obligate dimeric class C GPCR, suggesting an asymmetric, stepwise allosteric activation mechanism.
- Subjects
ALLOSTERIC regulation; G protein coupled receptors; GLUTAMATE receptors; G proteins; MARKOV processes
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51999-y