Structural basis and physiological significance of non-canonical Gs coupling to the melatonin MT1 receptor

Abstract

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 1 and MT 2 are prototypical G i/o -coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT 1 , but not MT 2 , couples also to G s proteins in vitro and activates the G s /cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solve the cryo–electron microscopy structure of the melatonin-MT 1 -G s complex at 3.0 Å resolution, which reveals a distinct binding mode compared to the MT 1 –G i complex. The third intracellular loop of MT 1 emerges as a key stabilizer for G s coupling. This structure of a GPCR primarily coupling to G i , here in complex with G s , provides structural and functional insights into G protein selectivity and circadian switch of G protein coupling.