Author information

¹Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.

²Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany.

³Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.

⁴Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany.

⁵German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site, Giessen, Germany.

⁶Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA. koss@bsd.uchicago.edu.

⁷Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany. Stephan.Urban@med.uni-heidelberg.de.

⁸German Center for Infection Research (DZIF) - partner site Heidelberg, Heidelberg, Germany. Stephan.Urban@med.uni-heidelberg.de.

⁹Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany. Dieter.Glebe@viro.med.uni-giessen.de.

¹⁰German Center for Infection Research (DZIF) - Giessen-Marburg-Langen Partner Site, Giessen, Germany. Dieter.Glebe@viro.med.uni-giessen.de.

¹¹Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany. Joachim.M.Geyer@vetmed.uni-giessen.de.

¹²Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland. locher@mol.biol.ethz.ch.

Abstract

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.