8hrx

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Cryo-EM structure of human NTCP-myr-preS1-YN9048Fab complex

Structural highlights

8hrx is a 4 chain structure with sequence from Hepatitis B virus, Homo sapiens and Ondatra zibethicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.89Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NTCP_HUMAN Familial hypercholanemia. The disease is caused by variants affecting the gene represented in this entry.

Function

NTCP_HUMAN As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It is strictly dependent on the extracellular presence of sodium (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate (PubMed:14660639, PubMed:34060352). Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321).[1] [2] [3] [4] [5] (Microbial infection) Acts as a receptor for hepatitis B virus.[6]

Publication Abstract from PubMed

Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus specifically infecting hepatocytes. Myristoylated preS1 domain of the HBV large surface protein binds to the host receptor sodium-taurocholate cotransporting polypeptide (NTCP), a hepatocellular bile acid transporter, to initiate viral entry. Here, we report the cryogenic-electron microscopy structure of the myristoylated preS1 (residues 2-48) peptide bound to human NTCP. The unexpectedly folded N-terminal half of the peptide embeds deeply into the outward-facing tunnel of NTCP, whereas the C-terminal half formed extensive contacts on the extracellular surface. Our findings reveal an unprecedented induced-fit mechanism for establishing high-affinity virus-host attachment and provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.

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 Mar;31(3):447-454. doi: 10.1038/s41594-023-01191-5. , Epub 2024 Jan 17. PMID:38233573[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP.
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References

  1. ↑ Ho RH, Leake BF, Roberts RL, Lee W, Kim RB. Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem. 2004 Feb 20;279(8):7213-22. doi: 10.1074/jbc.M305782200. Epub 2003, Dec 2. PMID:14660639 doi:http://dx.doi.org/10.1074/jbc.M305782200
  2. ↑ Vaz FM, Paulusma CC, Huidekoper H, de Ru M, Lim C, Koster J, Ho-Mok K, Bootsma AH, Groen AK, Schaap FG, Oude Elferink RP, Waterham HR, Wanders RJ. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology. 2015 Jan;61(1):260-7. doi: 10.1002/hep.27240. Epub 2014 Aug 25. PMID:24867799 doi:http://dx.doi.org/10.1002/hep.27240
  3. ↑ Floerl S, Kuehne A, Geyer J, Brockmoeller J, Tzvetkov MV, Hagos Y. Functional and Pharmacological Comparison of Human and Mouse Na(+)/Taurocholate Cotransporting Polypeptide (NTCP). SLAS Discov. 2021 Sep;26(8):1055-1064. PMID:34060352 doi:10.1177/24725552211017500
  4. ↑ Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest. 1994 Mar;93(3):1326-31. PMID:8132774 doi:10.1172/JCI117091
  5. ↑ Kunst RF, Verkade HJ, Oude Elferink RPJ, van de Graaf SFJ. Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology. Hepatology. 2021 Jun;73(6):2577-2585. PMID:33222321 doi:10.1002/hep.31651
  6. ↑ Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012 Nov 13;1:e00049. doi: 10.7554/eLife.00049. PMID:23150796 doi:http://dx.doi.org/10.7554/eLife.00049
  7. ↑ 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. Structural basis of hepatitis B virus receptor binding. Nat Struct Mol Biol. 2024 Mar;31(3):447-454. PMID:38233573 doi:10.1038/s41594-023-01191-5

Contents


PDB ID 8hrx

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