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TitleCryo-EM structure of the human MT-G signaling complex.
Journal, issue, pagesNat Struct Mol Biol, Vol. 28, Issue 8, Page 694-701, Year 2021
Publish dateAug 5, 2021
AuthorsHiroyuki H Okamoto / Hirotake Miyauchi / Asuka Inoue / Francesco Raimondi / Hirokazu Tsujimoto / Tsukasa Kusakizako / Wataru Shihoya / Keitaro Yamashita / Ryoji Suno / Norimichi Nomura / Takuya Kobayashi / So Iwata / Tomohiro Nishizawa / Osamu Nureki /
PubMed AbstractMelatonin receptors (MT and MT) transduce inhibitory signaling by melatonin (N-acetyl-5-methoxytryptamine), which is associated with sleep induction and circadian rhythm modulation. Although recently ...Melatonin receptors (MT and MT) 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 MT and MT elucidated the basis of ligand entry and recognition, the ligand-induced MT rearrangement leading to G-coupling remains unclear. Here we report a cryo-EM structure of the human MT-G 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-coupled receptors, MT exhibits a large outward movement of TM6, which is considered a specific feature of G-coupled receptors. Structural comparison of G and G complexes demonstrated conformational diversity of the C-terminal entry of the G protein, suggesting loose and variable interactions at the end of the α5 helix of G protein. These notions, together with our biochemical and computational analyses, highlight variable binding modes of Gα and provide the basis for the selectivity of G-protein signaling.
External linksNat Struct Mol Biol / PubMed:34354246
MethodsEM (single particle)
Resolution3.3 Å
Structure data

EMDB-30627, PDB-7db6:
human melatonin receptor MT1 - Gi1 complex
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-JEV:
N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide / medication, agonist*YM / Ramelteon

Source
  • homo sapiens (human)
  • rattus rattus (black rat)
  • bos taurus (cattle)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / gpcr / g-protein / complex

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