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

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 a...

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Hauptverfasser: Liu, Hongtao (VerfasserIn) , Zakrzewicz, Dariusz (VerfasserIn) , Nosol, Kamil (VerfasserIn) , Irobalieva, Rossitza N. (VerfasserIn) , Mukherjee, Somnath (VerfasserIn) , Bang-Sørensen, Rose (VerfasserIn) , Goldmann, Nora (VerfasserIn) , Kunz, Sebastian (VerfasserIn) , Rossi, Lorenzo (VerfasserIn) , Kossiakoff, Anthony A. (VerfasserIn) , Urban, Stephan (VerfasserIn) , Glebe, Dieter (VerfasserIn) , Geyer, Joachim (VerfasserIn) , Locher, Kaspar (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 20 March 2024
In: Nature Communications
Year: 2024, Jahrgang: 15, Pages: 1-13
ISSN:2041-1723
DOI:10.1038/s41467-024-46706-w
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-024-46706-w
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-024-46706-w
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 09.07.2024
Beschreibung:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-46706-w

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