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    Home > Biochemistry News > Biotechnology News > The latest paper from Nature Communications of Sichuan University: Molecular mechanism of ligand entry into Sigma-1 receptor pathway

    The latest paper from Nature Communications of Sichuan University: Molecular mechanism of ligand entry into Sigma-1 receptor pathway

    • Last Update: 2022-04-25
    • Source: Internet
    • Author: User
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      On March 10, 2022, the team of researchers Sun Ziyi and Zhou Xiaoming of the State Key Laboratory of Biotherapy/Rare Disease Center/Department of Integrative Medicine, West China Hospital, Sichuan University published online in Nature Communications entitled "An open-like conformation of the sigma -1 receptor reveals its ligand entry pathway", which revealed the molecular mechanism of ligand entry into sigma-1 receptor through PATH2 pathway
    .
    The results of this study have important guiding significance for targeting and regulating the function of σ1R to treat a variety of diseases

    .

      Dr.
    Meng Fuhui and doctoral student Xiao Yang of the research group are the co-first authors, and master student Ji Yujia participated in the research

    .
    West China Hospital of Sichuan University is the first author

    .


      Sigma-1 receptor (σ1R) is a class of non-opioid transmembrane protein receptors, mainly located in the endoplasmic reticulum membrane of cells, distributed in most organs and tissues of the human body, and mediates cell survival and various physiological activities.

    .
    σ1R dysfunction is associated with a variety of diseases such as neurodegenerative diseases, cancer,

    etc.
    The crystal structure of the human sigma-1 receptor (hσ1R) published in 2016 (Figure 1 left) shows that the σ1R structure is in the form of a homotrimer, each monomer contains an amino-terminal primary transmembrane helix (α1), a middle The β-barrel containing the ligand binding site and the V-shaped double helix bundle (α4/α5) with the carboxyl terminus close to the membrane

    .
    There are two possible ways for ligands to enter σ1R (right in Figure 1): The first possibility (PATH1) is that ligands enter σ1R through the bottom of the β-barrel, and this process involves the opening and reassembly of the β-barrel.
    while the second possibility (PATH2) holds that the ligand enters the ligand-binding site of σ1R through the opening between the α4 and α5 helices

    .
    The ligand entry pathway of σ1R has been controversial due to the lack of clear experimental evidence

    .




     

      Figure 1.
    Three-dimensional conformation of σ1R and two possible pathways by which ligands enter and exit the receptor
    .
    From the original Figure 1

    .



     

      This study used X-ray crystallography to resolve for the first time the openness of Xenopus laevis σ1R (xlσ1R) to bind endogenous ligands (presumed) and exogenous ligands (agonist PRE-084, antagonist S1RA), respectively / Closed high precision 3D structure
    .
    The closed structure of xlσ1R is similar to that of hσ1R, which is a homotrimer (Fig.
    2 left), but its crystal packing method and the structure of the receptor-ligand complex obtained by soaking the xlσ1R crystal with ligands show that the soaked ligand cannot Enter xlσ1R via PATH1

    .




     

      Figure 2.
    Open/closed conformation of σ1R and opening of the α4/α5 helix
    .
    From the original Figure 3

    .



     

      On the other hand, the α4 helix in the open structure of xlσ1R undergoes rotational displacement, and the tyrosine side chain at position 203 on the α5 helix rotates inward, forming an opening that allows the passage of ligands (Fig.
    2 right)

    .
    The researchers designed a disulfide bond mutant (L179C/Y203C) to limit the relative movement of the α4/α5 helix, and used isothermal titration calorimetry (ITC) to measure the binding parameters of the ligand to xlσ1R, and the results showed that the ligand binding was limited (Fig.
    3)

    .
    In addition, increasing the steric hindrance at the opening by chemical modification found that the degree of ligand-receptor binding restriction was consistent with the degree of steric hindrance at the opening

    .
    This result provides strong evidence for ligand entry into σ1R via PATH2

    .


      Figure 3.
    xlσ1R entry mutation and ligand binding experiments
    .
    From the original
    Figure 4
    .

      In conclusion, this study resolves the open structure of Xenopus laevis σ1R by X-ray crystallography, which supports the entry of σ1R ligands into the receptor β-barrel through the opening between the α4 and α5 helices (PATH2 pathway).
    body binding site

    .
    ITC measured the changes of binding parameters between receptors and ligands in the normal and restricted states of this opening, which further verified the thesis of the article

    .
    The results of this study have important guiding significance for targeting and regulating the function of σ1R to treat a variety of diseases

    .

      Original link: https://doi.
    org/10.
    1038/s41467-022-28946-w
     



     

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