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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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Main Authors: Liu, Hongtao (Author) , Zakrzewicz, Dariusz (Author) , Nosol, Kamil (Author) , Irobalieva, Rossitza N. (Author) , Mukherjee, Somnath (Author) , Bang-Sørensen, Rose (Author) , Goldmann, Nora (Author) , Kunz, Sebastian (Author) , Rossi, Lorenzo (Author) , Kossiakoff, Anthony A. (Author) , Urban, Stephan (Author) , Glebe, Dieter (Author) , Geyer, Joachim (Author) , Locher, Kaspar (Author)
Format: Article (Journal)
Language:English
Published: 20 March 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-13
ISSN:2041-1723
DOI:10.1038/s41467-024-46706-w
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-024-46706-w
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-024-46706-w
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 09.07.2024
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-46706-w

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