Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. With approximately 1. HBV, a small, enveloped DNA virus, causes acute and chronic infection of the liver and the chronic form, in particular, significantly contributes to the overall burden of liver-related diseases, such as cirrhosis and hepatocellular carcinoma HCC 2 , 3.
NTCP SLC10A1 , a member of the solute carrier transporter family, is one of four transporters involved in the enterohepatic circulation of bile salts 15 , 16 , Its function is linked to maintaining bile salt homeostasis, essential for the digestion and absorption of dietary fats In , four independent studies reported structures of NTCP, revealing nine transmembrane helices TMs arranged in two domains, termed panel and core 20 , 21 , 22 , Two of these helices create a crossing motif X-motif , near which two sodium ion binding sites are located The highest-resolution structure revealed the binding sites for two bile salt molecules in a continuous tunnel that links the extracellular and cytoplasmic side of the basolateral membrane Bile salt uptake into hepatocytes is mediated by NTCP, located in the basolateral membrane of hepatocytes.
HBV interacts with heparan sulfate proteoglycans HSPGs by low-affinity attachment, followed by interaction with the NTCP receptor protein, initiating the entry of viral particles into the hepatocytes. This process can be inhibited by bulevirtide, a preS1-derived peptide. They contain the same C-terminus but differ by N-terminal additions and N-glycosylation status.
The SHBs contain four transmembrane helices that are embedded in the viral membrane and are linked by intra- and intermolecular disulfide bridges. During protein synthesis, the LHBs undergo a posttranslational modification via myristoylation at a conserved glycine residue Gly2 in the preS1-domain 24 , 28 , The exact mechanism of NTCP-mediated virus entry remains elusive; however, it is thought to occur via endocytosis, which is known to recruit various host factors for entry initiation 34 , During active HBV infections, two distinct species of viral particles are produced: infectious virus particles and a far larger excess of non-infectious subviral particles SVPs 36 , 37 , Whilst both species contain all three viral envelope proteins, allowing for recognition and binding to NTCP as a receptor, SVPs lack genetic material and are therefore not infectious 38 , NTCP was shown to transport bile salts in a strictly sodium-dependent manner 46 and we also observed that a fluorescently labeled taurocholate derivative 4-nitrobenzooxa-1,3-diazole-taurocholic acid, NBD-TC is taken up into NTCP-expressing HEK cells in a sodium-dependent manner Fig.
In both preparations the preS1-containing LHBs can be clearly detected by silver-stained polyacrylamide gel electrophoresis, although patient K showed a more prominent signal than patient ID1 Fig. At high concentrations, BLV fully abolished transport. The BLV peptide is colored in three sections: myristoylated glycine magenta , plug orange , and string blue.
