7vag

From Proteopedia

Jump to: navigation, search

Cryo-EM structure of human NTCP complexed with YN69202Fab in the presence of myristoylated preS1 peptide

Structural highlights

7vag is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.32Å
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

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(1,2). 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 hepatocytes(3). 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.

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. 2022 Jun;606(7916):1021-1026. doi: 10.1038/s41586-022-04845-4. Epub 2022 , May 17. PMID:35580629[7]

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

Loading citation details..
Citations
reviews cite this structure
-1 more
other articles
No citations found

See Also

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, 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. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun;606(7916):1021-1026. PMID:35580629 doi:10.1038/s41586-022-04845-4

Contents


PDB ID 7vag

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/7vag"
Personal tools