钠依赖性胆汁盐摄入肝脏的结构基础

StephenW

钠依赖性胆汁盐摄入肝脏的结构基础
Kapil Goutam 1 2，Francesco S Ielasi 2，Els Pardon 3 4，Jan Steyaert 3 4，Nicolas Reyes 5 6
隶属关系
隶属关系

    1
    波尔多大学欧洲化学与生物学研究所膜蛋白机制组，CNRS-UMR5234，法国佩萨克。
    2
    膜蛋白机制单元，巴斯德研究所，巴黎，法国。
    3
    布鲁塞尔结构生物学，布鲁塞尔自由大学，VUB，布鲁塞尔，比利时。
    4
    VIB-VUB 结构生物学中心，VIB，布鲁塞尔，比利时。
    5
    波尔多大学欧洲化学与生物学研究所膜蛋白机制组，CNRS-UMR5234，法国佩萨克。 [email protected]。
    6
    膜蛋白机制单元，巴斯德研究所，巴黎，法国。 [email protected]。

    PMID：35545671 DOI：10.1038/s41586-022-04723-z

抽象的

肝脏从血液中吸收胆汁盐以产生胆汁，从而能够吸收亲脂性营养物质并排泄代谢物和药物1。人 Na+-牛磺胆酸盐协同转运多肽 (NTCP) 是肝脏中主要的胆盐摄取系统。 NTCP 还是人类乙型和丁型肝炎病毒 2,3 (HBV/HDV) 的细胞进入受体，并已成为抗病毒药物的重要靶点 4。然而，NTCP 转运和病毒受体功能的分子机制仍未完全了解。在这里，我们展示了与纳米体复合的人类 NTCP 的低温电子显微镜结构，揭示了其运输周期的关键构象。 NTCP 经历了一个构象转变，打开了一个宽的跨膜孔，作为胆汁盐的运输途径，并将 HBV/HDV 结合的关键决定性残基暴露在细胞外。一种稳定孔闭合和内向状态的纳米体会损害对 HBV/HDV 受体结合域 preS1 的识别，这表明病毒对 NTCP 转运循环的对外开放构象的结合选择性优于内向构象。这些结果为 NTCP“门控孔”转运和 HBV/HDV 受体识别机制提供了分子见解，并有望帮助开发针对 NTCP 的肝病疗法。

© 2022。作者。

StephenW

Structural basis of sodium-dependent bile salt uptake into the liver
Kapil Goutam  1   2 , Francesco S Ielasi  2 , Els Pardon  3   4 , Jan Steyaert  3   4 , Nicolas Reyes  5   6
Affiliations
Affiliations

    1
    Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Pessac, France.
    2
    Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France.
    3
    Structural Biology Brussels, Vrije Universiteit Brussel, VUB, Brussels, Belgium.
    4
    VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
    5
    Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Pessac, France. [email protected].
    6
    Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France. [email protected].

    PMID: 35545671 DOI: 10.1038/s41586-022-04723-z

Abstract

The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs1. Human Na+-taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses2,3 (HBV/HDV), and has emerged as an important target for antiviral drugs4. However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP 'gated-pore' transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP.

© 2022. The Author(s).

StephenW

https://www.nature.com/articles/s41586-022-04723-z.pdf