期刊
NATURE
卷 606, 期 7916, 页码 1015-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04723-z
关键词
-
资金
- (NTCPEM-Nb87)
- CACSICE infrastructure grant [ANR-11-EQPX-008]
- European Research Council (ERC) under European Union [771965]
- ANRS [17125/18141]
- IDEX Senior Chair Universite de Bordeaux
- Region Nouvelle-Aquitaine [8166910, 2036, 15056, 7370, 7111]
- European Research Council (ERC) [771965] Funding Source: European Research Council (ERC)
This study provides molecular insights into the key conformations of NTCP transport cycle and the recognition mechanisms of HBV/HDV receptors. These findings are expected to contribute to the development of liver disease therapies targeting NTCP.
The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs(1). Human Na+-taurocholate co-transporting polypeptide (NTCP) isthe main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses(2,3) (HBV/HDV), and has emerged as an important target for antiviral drugs(1). 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 itstransport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves asthe transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside ofthe cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition ofthe HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity ofthe viruses for open-to-outside over inward-facing conformations ofthe 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据