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An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway

Author

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  • Fuhui Meng

    (West China Hospital, Sichuan University)

  • Yang Xiao

    (West China Hospital, Sichuan University)

  • Yujia Ji

    (West China Hospital, Sichuan University)

  • Ziyi Sun

    (West China Hospital, Sichuan University)

  • Xiaoming Zhou

    (West China Hospital, Sichuan University)

Abstract

The sigma-1 receptor (σ1R) is a non-opioid transmembrane receptor which has been implicated in many diseases, including neurodegenerative disorders and cancer. After more than forty years of research, substantial progress has been made in understanding this unique receptor, yet the molecular mechanism of its ligand entry pathway remains uncertain. Published structures of human σ1R reveal its homotrimeric organization of a cupin-fold β-barrel body that contains the ligand binding site, a carboxy-terminal V-shaped two-helix bundle, and a single amino-terminal transmembrane helix, while simulation studies have suggested a ligand entry pathway that is generated by conformational rearrangements of the cupin-fold domain. Here, we present multiple crystal structures, including an open-like conformation, of σ1R from Xenopus laevis. Together with functional binding analysis our data suggest that access to the σ1R ligand binding site is likely achieved by protein conformational changes that involve the carboxy-terminal two-helix bundle, rather than structural changes in the cupin-fold domain.

Suggested Citation

  • Fuhui Meng & Yang Xiao & Yujia Ji & Ziyi Sun & Xiaoming Zhou, 2022. "An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28946-w
    DOI: 10.1038/s41467-022-28946-w
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    References listed on IDEAS

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    1. Xiaoming Zhou & Elena J. Levin & Yaping Pan & Jason G. McCoy & Ruchika Sharma & Brian Kloss & Renato Bruni & Matthias Quick & Ming Zhou, 2014. "Structural basis of the alternating-access mechanism in a bile acid transporter," Nature, Nature, vol. 505(7484), pages 569-573, January.
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    Cited by:

    1. Chunting Fu & Yang Xiao & Xiaoming Zhou & Ziyi Sun, 2024. "Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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