Structural basis and physiological significance of non-canonical G<sub>s</sub> coupling to the melatonin MT<sub>1</sub> receptor.
basic_science · Level V
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- Record sourced from PubMed, PMID 42168230.
- Also identified by DOI 10.1038/s41467-026-73555-6.
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Abstract
G protein-coupled receptors (GPCRs) transduce extracellular stimuli into intracellular signals by coupling to various heterotrimeric G proteins. However, the rules governing G protein preference remain largely elusive. MT<sub>1</sub> and MT<sub>2</sub> are prototypical G<sub>i/o</sub>-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT<sub>1</sub>, but not MT<sub>2</sub>, couples also to G<sub>s</sub> proteins in vitro and activates the G<sub>s</sub>/cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solve the cryo-electron microscopy structure of the melatonin-MT<sub>1</sub>-G<sub>s</sub> complex at 3.0 Å resolution, which reveals a distinct binding mode compared to the MT<sub>1</sub>-G<sub>i</sub> complex. The third intracellular loop of MT<sub>1</sub> emerges as a key stabilizer for G<sub>s</sub> coupling. This structure of a GPCR primarily coupling to G<sub>i</sub>, here in complex with G<sub>s</sub>, provides structural and functional insights into G protein selectivity and circadian switch of G protein coupling.