7VAD

Cryo-EM structure of human NTCP complexed with YN69202Fab

Summary for 7VAD

• Entry DOI: 10.2210/pdb7vad/pdb
• EMDB information: 31837
• Descriptor: Sodium/bile acid cotransporter, Fab heavy chain from antibody IgG clone number YN69202, Fab light chain from antibody IgG clone number YN69202 (3 entities in total)
• Functional Keywords: hepatitis b virus (hbv), host entry receptor, bile acid transporter, taurocholate, na+-coupled symporter, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 89040.52

Authors

Asami, J.,Shimizu, T.,Ohto, U. (deposition date: 2021-08-29, release date: 2022-05-25, Last modification date: 2024-10-09)

Primary citation

Asami, J.,Kimura, K.T.,Fujita-Fujiharu, Y.,Ishida, H.,Zhang, Z.,Nomura, Y.,Liu, K.,Uemura, T.,Sato, Y.,Ono, M.,Yamamoto, M.,Noda, T.,Shigematsu, H.,Drew, D.,Iwata, S.,Shimizu, T.,Nomura, N.,Ohto, U.
Structure of the bile acid transporter and HBV receptor NTCP.
Nature, 606:1021-1026, 2022

PubMed Abstract: Chronic infection with hepatitis B virus (HBV) affects more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma, and results in an estimated 820,000 deaths annually. For HBV infection to be established, a molecular interaction is required between the large glycoproteins of the virus envelope (known as LHBs) and the host entry receptor sodium taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from the blood to hepatocytes. However, the molecular basis for the virus-transporter interaction is poorly understood. Here we report the cryo-electron microscopy structures of human, bovine and rat NTCPs in the apo state, which reveal the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-electron microscopy structure of human NTCP in the presence of the myristoylated preS1 domain of LHBs, together with mutation and transport assays, suggest a binding mode in which preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Our preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Together, our findings provide a structural framework for HBV recognition and a mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.

PubMed: 35580629
DOI: 10.1038/s41586-022-04845-4

Experimental method

ELECTRON MICROSCOPY (3.41 Å)