乙型肝炎病毒
病毒学
运输机
糖蛋白
肝细胞癌
病毒
细胞外
化学
生物
生物化学
癌症研究
基因
作者
Jinta Asami,Kanako Kimura,Yoko Fujita-Fujiharu,Hanako Ishida,Zhikuan Zhang,Yoshihiro Nomura,Kehong Liu,T. Uemura,Yuichi Sato,Masashi Ono,Masaki Yamamoto,Takeshi Noda,Hideki Shigematsu,David Drew,So Iwata,Toshiyuki Shimizu,Umeharu Ohto
出处
期刊:Nature
[Springer Nature]
日期:2022-05-17
卷期号:606 (7916): 1021-1026
被引量:42
标识
DOI:10.1038/s41586-022-04845-4
摘要
Chronic infection with hepatitis B virus (HBV), affecting more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma and results in an estimated 820,000 human deaths annually1,2. Establishment of HBV infection requires a molecular interaction between the virus envelope glycoprotein L (LHBs) and the host entry receptor sodium-taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from blood to hepatocytes 3. However, the molecular basis for the virus-transporter interaction is poorly understood. Here, we report the cryo-electron microscopy (cryo-EM) structures of human, bovine, and rat NTCPs in the apo state, which reveals the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-EM structure of human NTCP in the presence of myristoylated preS1 domain of LHBs together with mutation and transport assays suggest a binding mode whereby preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Importantly, the preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Taken together, our findings provide structural framework for HBV recognition and for mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.
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