Nature Communications volume 15, Article number: 2476 (2024)
Hongtao Liu, Dariusz Zakrzewicz, Kamil Nosol, Rossitza N Irobalieva, Somnath Mukherjee, Rose Bang-Sørensen, Nora Goldmann, Sebastian Kunz, Lorenzo Rossi, Anthony A Kossiakoff, Stephan Urban, Dieter Glebe, Joachim Geyer, Kaspar P Locher
PMID: 38509088 PMCID: PMC10954734 DOI: 10.1038/s41467-024-46706-w
Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor’s extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.