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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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

摘要

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. MT1 and MT2 are prototypical Gi/o-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT1, but not MT2, couples also to Gs proteins in vitro and activates the Gs/cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solve the cryo–electron microscopy structure of the melatonin-MT1-Gs complex at 3.0 Å resolution, which reveals a distinct binding mode compared to the MT1–Gi complex. The third intracellular loop of MT1 emerges as a key stabilizer for Gs coupling. This structure of a GPCR primarily coupling to Gi, here in complex with Gs, provides structural and functional insights into G protein selectivity and circadian switch of G protein coupling.