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

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.

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Publication Details

Journal
Nature Communications
Published
2026-05-21
DOI
https://doi.org/10.1038/s41467-026-73555-6
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
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article

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

Atsuro Oishi, Tsukasa Kusakizako, Osamu Nureki, Miki Nagase et al.
Nature Communications
Receptor Mechanisms and Signaling
article

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

Atsuro Oishi, Tsukasa Kusakizako, Osamu Nureki, Miki Nagase, Irina G. Tikhonova, Keisuke Ikegami, Julie Dam, Ronan McHugh, Erika Cecon, Hiroyuki Okamoto, Bernard Masri, Akifumi Takaki, Ralf Jockers, Kazuhiro Kobayashi, Angeliki Karamitri
article en

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.

Nature Communications
Queen's University Belfast (GB), Centre National de la Recherche Scientifique (FR), Kyushu University (JP), Inserm (FR), Aichi Medical University (JP), Kyorin University (JP), Université Paris Cité (FR), Institut Cochin (FR), The University of Tokyo (JP)
Openalex Percentile: Top 9%
Receptor Mechanisms and Signaling
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