Biological Sciences Division
Published March 20, 2024 | Version v1
Journal article Open

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

Creators

  • 1. ETH Zürich
  • 2. Justus Liebig University Giessen
  • 3. University of Chicago
  • 4. Heidelberg University

Description

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.

Data availability

The electron microscopy density map of the NTCP-BLV-Fab3-Nb complex has been deposited in the Electron Microscopy Data Bank (EMDB) under accession code EMD-19440. The refined model of the complex has been deposited in the Protein Data Bank under accession code 8RQF. Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-024-46706-w
Other
oai:uchicago.tind.io:11445

Funding

Swiss National Science Foundation (SNSF)
189111
Swiss National Science Foundation (SNSF)
214834
Deutsche Forschungsgemeinschaft (DFG)
SFB 1021
National Institutes of Health
GM117372
Deutsches Zentrum für Infektionsforschung (DZIF, German Center for Infection Research)
TTU 05.709

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Biochemistry and Molecular Biology