Cryo-EM structure of the human MT1-Gi signaling complex

Nat Struct Mol Biol. 2021 Aug;28(8):694-701. doi: 10.1038/s41594-021-00634-1.

Hiroyuki H Okamoto ¹, Hirotake Miyauchi ¹, Asuka Inoue ², Francesco Raimondi ³, Hirokazu Tsujimoto ⁴, Tsukasa Kusakizako ¹, Wataru Shihoya ¹, Keitaro Yamashita ¹ ⁵, Ryoji Suno ⁶, Norimichi Nomura ⁴, Takuya Kobayashi ⁶, So Iwata ⁴ ⁷, Tomohiro Nishizawa ⁸ ⁹, Osamu Nureki ¹⁰

Affiliations

1 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
2 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. [email protected].
3 Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy.
4 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
6 Department of Medical Chemistry, Kansai Medical University, Hirakata, Japan.
7 RIKEN SPring-8 Center, Sayo, Japan.
8 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. [email protected].
9 Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan. [email protected].
10 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. [email protected].

PMID: 34354246 DOI: 10.1038/s41594-021-00634-1

Abstract

Melatonin receptors (MT₁ and MT₂) transduce inhibitory signaling by melatonin (N-acetyl-5-methoxytryptamine), which is associated with sleep induction and circadian rhythm modulation. Although recently reported crystal structures of ligand-bound MT₁ and MT₂ elucidated the basis of ligand entry and recognition, the ligand-induced MT₁ rearrangement leading to G_i-coupling remains unclear. Here we report a cryo-EM structure of the human MT₁-G_i signaling complex at 3.3 Å resolution, revealing melatonin-induced conformational changes propagated to the G-protein-coupling interface during activation. In contrast to Other G_i-coupled receptors, MT₁ exhibits a large outward movement of TM6, which is considered a specific feature of G_s-coupled receptors. Structural comparison of G_i and G_s complexes demonstrated conformational diversity of the C-terminal entry of the G_i protein, suggesting loose and variable interactions at the end of the α5 helix of G_i protein. These notions, together with our biochemical and computational analyses, highlight variable binding modes of Gα_i and provide the basis for the selectivity of G-protein signaling.

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