Structure of hepatitis B/D antiviral drug Bulevirtide bound to its receptor protein NTCP
Liu, H.; Zakrzewicz, D.; Nosol, K.; Irobalieva, R. N.; Mukherjee, S.; Bang-Soerensen, R.; Goldmann, N.; Kunz, S.; Rossi, L.; Kossiakoff, A. A.; Urban, S.; Glebe, D.; Geyer, J.; Locher, K. P.
Show abstract
Cellular entry of the hepatitis B and D viruses (HBV/HDV) require binding of the viral surface polypeptide preS1 to the hepatobiliary transporter NTCP. This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. 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 receptors 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.
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