メラトニン受容体MT1が複数の細胞内シグナルを使い分けるしくみを解明

2026-06-22 杏林大学

＜関連情報＞

• https://www.kyorin-u.ac.jp/univ/news/3922/
• https://www.nature.com/articles/s41467-026-73555-6

メラトニンMT1受容体への非標準的なGs結合の構造的基盤と生理学的意義 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
Nature Communications  Published:21 May 2026
DOI:https://doi.org/10.1038/s41467-026-73555-6  Unedited version

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.