小柯机器人

日本东京大学Umeharu Ohto和日本京都大学Norimichi Nomura团队共同合作近期取得重要工作进展。他们研究发现胆汁酸转运蛋白NTCP的结构对乙型肝炎病毒进入至关重要。该项研究成果2022年5月17日在线发表于《自然》杂志上。

在这里，研究人员报告了人类、牛和大鼠NTCPs在apo状态下的低温电子显微镜（cryo-EM）结构，它揭示了跨膜隧道的存在和底物的可能运输途径。

此外，人类NTCP在LHBs的肉豆蔻酰化preS1结构域存在下的低温电镜结构以及突变和运输试验分析表明了一种结合模式，即preS1和底物竞争NTCP中细胞外通道的开口。重要的是，preS1域相互作用分析能够对人类NTCP中自然发生的HBV不敏感突变进行机理解释。综上所述，他们的研究结果为HBV识别和哺乳动物NTCPs对钠依赖性胆汁酸易位的机制的理解提供了结构框架。

据介绍，慢性乙型肝炎病毒 (HBV) 感染在全球影响超过2.9亿人，是肝硬化和肝细胞癌的主要原因，估计每年导致82万人死亡。HBV感染的建立需要病毒包膜糖蛋白L(LHBs)与宿主进入受体钠-牛磺胆酸共转运多肽(NTCP)之间的分子相互作用，NTCP是一种从血液到肝细胞的钠依赖性胆汁酸转运蛋白。然而，目前对于病毒-转运蛋白相互作用分子基础尚不清楚。

附：英文原文

Title: Structure of bile acid transporter NTCP crucial for hepatitis B virus entry

Author: Asami, Jinta, Kimura, Kanako Terakado, Fujita-Fujiharu, Yoko, Ishida, Hanako, Zhang, Zhikuan, Nomura, Yayoi, Liu, Kehong, Uemura, Tomoko, Sato, Yumi, Ono, Masatsugu, Yamamoto, Masaki, Noda, Takeshi, Shigematsu, Hideki, Drew, David, Iwata, So, Shimizu, Toshiyuki, Nomura, Norimichi, Ohto, Umeharu

Issue&Volume: 2022-05-17

Abstract: 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.

DOI: 10.1038/s41586-022-04845-4

Source: https://www.nature.com/articles/s41586-022-04845-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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