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Structure of the bile acid transporter and HBV receptor NTCP.

Asami J, Kimura KT, 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
Nature 606 1021-1026 (2022)
Related entries: 7vad, 7vae, 7vaf, 7vag

Cited: 19 times
EuropePMC logo PMID: 35580629

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 annually1,2. 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 hepatocytes3. 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.

Reviews - 7wsi mentioned but not cited (1)

  1. Role of the Sodium-Dependent Organic Anion Transporter (SOAT/SLC10A6) in Physiology and Pathophysiology. Wannowius M, Karakus E, Aktürk Z, Breuer J, Geyer J. Int J Mol Sci 24 9926 (2023)

Articles - 7wsi mentioned but not cited (2)

  1. The metabolic adaptation of bile acids and cholesterol after biliary atresia in lamprey via transcriptome-based analysis. Zhang Q, Pan J, Zhu Y, Liu J, Pang Y, Li J, Han P, Gou M, Li J, Su P, Li Q, Chi Y. Heliyon 9 e19107 (2023)
  2. Tyrosine 146 of the Human Na+/Taurocholate Cotransporting Polypeptide (NTCP) Is Essential for Its Hepatitis B Virus (HBV) Receptor Function and HBV Entry into Hepatocytes. Zakrzewicz D, Leidolf R, Kunz S, Müller SF, Neubauer A, Leiting S, Goldmann N, Lehmann F, Glebe D, Geyer J. Viruses 14 1259 (2022)


Reviews citing this publication (7)

  1. Advances in Immunotherapy for Hepatitis B. Wang D, Fu B, Wei H. Pathogens 11 1116 (2022)
  2. In vitro cell culture models to study hepatitis B and D virus infection. Guo H, Urban S, Wang W. Front Microbiol 14 1169770 (2023)
  3. Bile Acid Network and Vascular Calcification-Associated Diseases: Unraveling the Intricate Connections and Therapeutic Potential. Wang C, Ma Q, Yu X. Clin Interv Aging 18 1749-1767 (2023)
  4. Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Thiyagarajah K, Basic M, Hildt E. Viruses 15 1687 (2023)
  5. Hepatitis B Virus Epsilon (ε) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target. Olenginski LT, Attionu SK, Henninger EN, LeBlanc RM, Longhini AP, Dayie TK. Viruses 15 1913 (2023)
  6. Key Factors for "Fishing" NTCP as a Functional Receptor for HBV and HDV. Yan H, Wang C. Viruses 15 512 (2023)
  7. The Multiple Facets and Disorders of B Cell Functions in Hepatitis B Virus Infection. Ablikim D, Zeng X, Xu C, Zhao M, Yang X, Feng X, Liu J. J Clin Med 12 2000 (2023)

Articles citing this publication (9)

  1. Letter Studying severe long COVID to understand post-infectious disorders beyond COVID-19. Brodin P, Casari G, Townsend L, O'Farrelly C, Tancevski I, Löffler-Ragg J, Mogensen TH, Casanova JL, COVID Human Genetic Effort. Nat Med 28 879-882 (2022)
  2. Letter Structure of human NTCP reveals the basis of recognition and sodium-driven transport of bile salts into the liver. Liu H, Irobalieva RN, Bang-Sørensen R, Nosol K, Mukherjee S, Agrawal P, Stieger B, Kossiakoff AA, Locher KP. Cell Res 32 773-776 (2022)
  3. News Unlocking the secrets to human NTCP structure. Qi X, Li W. Innovation (Camb) 3 100294 (2022)
  4. A large expert-curated cryo-EM image dataset for machine learning protein particle picking. Dhakal A, Gyawali R, Wang L, Cheng J. Sci Data 10 392 (2023)
  5. ATP5B Is an Essential Factor for Hepatitis B Virus Entry. Ueda K, Suwanmanee Y. Int J Mol Sci 23 9570 (2022)
  6. Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation. Tremmel R, Nies AT, van Eijck BAC, Handin N, Haag M, Winter S, Büttner FA, Kölz C, Klein F, Mazzola P, Hofmann U, Klein K, Hoffmann P, Nöthen MM, Gaugaz FZ, Artursson P, Schwab M, Schaeffeler E. Int J Mol Sci 23 7468 (2022)
  7. Mechanism of substrate binding and transport in BASS transporters. Becker P, Naughton F, Brotherton D, Pacheco-Gomez R, Beckstein O, Cameron AD. Elife 12 RP89167 (2023)
  8. Screening of Membrane Protein Production by Comparison of Transient Expression in Insect and Mammalian Cells. Kaipa JM, Krasnoselska G, Owens RJ, van den Heuvel J. Biomolecules 13 817 (2023)
  9. Structural basis of hepatitis B virus receptor binding. Asami J, Park JH, Nomura Y, Kobayashi C, Mifune J, Ishimoto N, Uemura T, Liu K, Sato Y, Zhang Z, Muramatsu M, Wakita T, Drew D, Iwata S, Shimizu T, Watashi K, Park SY, Nomura N, Ohto U. Nat Struct Mol Biol (2024)


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