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

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

doi:10.1038/s41467-026-73555-6

Structural basis and physiological significance of non-canonical G_s coupling to the melatonin MT₁receptor

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^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

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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. MT₁ and MT₂ are prototypical G_i/o-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT₁, but not MT₂, 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-MT₁-G_s complex at 3.0 Å resolution, which reveals a distinct binding mode compared to the MT₁–G_i complex. The third intracellular loop of MT₁ 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.

Original language	English
Article number	6706
Number of pages	15
Journal	Nature Communications
Volume	17
DOIs	https://doi.org/10.1038/s41467-026-73555-6
Publication status	Published - 21 Jul 2026

Keywords

G protein-coupled receptors (GPCRs)
extracellular stimuli
non-canonical Gs

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10.1038/s41467-026-73555-6Licence: CC BY

Structural basis and physiological significance of non-canonical Gs coupling to the melatonin MT1 receptor
Copyright 2026 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 3.28 MBLicence: CC BY

Cite this

Oishi, A., Okamoto, H. H., Ikegami, K., McHugh, R., Masri, B., Kusakizako, T., Kobayashi, K., Takaki, A., Karamitri, A., Cecon, E., Dam, J., Nagase, M., Tikhonova, I. G., Nureki, O., & Jockers, R. (2026). Structural basis and physiological significance of non-canonical G_s coupling to the melatonin MT₁receptor. Nature Communications, 17, Article 6706. https://doi.org/10.1038/s41467-026-73555-6

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title = "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. 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{\textendash}electron microscopy structure of the melatonin-MT1-Gs complex at 3.0 {\AA} resolution, which reveals a distinct binding mode compared to the MT1{\textendash}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. ",

keywords = "G protein-coupled receptors (GPCRs), extracellular stimuli, non-canonical Gs",

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

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Oishi, A, Okamoto, HH, Ikegami, K, McHugh, R, Masri, B, Kusakizako, T, Kobayashi, K, Takaki, A, Karamitri, A, Cecon, E, Dam, J, Nagase, M, Tikhonova, IG, Nureki, O & Jockers, R 2026, 'Structural basis and physiological significance of non-canonical G_s coupling to the melatonin MT₁receptor', Nature Communications, vol. 17, 6706. https://doi.org/10.1038/s41467-026-73555-6

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T1 - Structural basis and physiological significance of non-canonical Gs coupling to the melatonin MT1 receptor

AU - Oishi, Atsuro

AU - Okamoto, Hiroyuki H.

AU - Ikegami, Keisuke

AU - McHugh, Ronan

AU - Masri, Bernard

AU - Kusakizako, Tsukasa

AU - Kobayashi, Kazuhiro

AU - Takaki, Akifumi

AU - Karamitri, Angeliki

AU - Cecon, Erika

AU - Dam, Julie

AU - Nagase, Miki

AU - Tikhonova, Irina G.

AU - Nureki, Osamu

AU - Jockers, Ralf

PY - 2026/7/21

Y1 - 2026/7/21

N2 - 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.

AB - 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.

KW - G protein-coupled receptors (GPCRs)

KW - extracellular stimuli

KW - non-canonical Gs

U2 - 10.1038/s41467-026-73555-6

DO - 10.1038/s41467-026-73555-6

M3 - Article

C2 - 42168230

SN - 2041-1723

VL - 17

JO - Nature Communications

JF - Nature Communications

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