8RQF

Cryo-EM structure of human NTCP-Bulevirtide complex

Summary for 8RQF

• Entry DOI: 10.2210/pdb8rqf/pdb
• EMDB information: 19440
• Descriptor: Sodium/bile acid cotransporter, Heavy chain of Fab3, Light chain of Fab3, ... (7 entities in total)
• Functional Keywords: hepatitis b/d virus receptor, bile salt transporter, drugs, inhibitor, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 105369.28

Authors

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. (deposition date: 2024-01-18, release date: 2024-03-27, Last modification date: 2024-10-23)

Primary citation

Liu, H.,Zakrzewicz, D.,Nosol, K.,Irobalieva, R.N.,Mukherjee, S.,Bang-Sorensen, R.,Goldmann, N.,Kunz, S.,Rossi, L.,Kossiakoff, A.A.,Urban, S.,Glebe, D.,Geyer, J.,Locher, K.P.
Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP.
Nat Commun, 15:2476-2476, 2024

PubMed 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.

PubMed: 38509088
DOI: 10.1038/s41467-024-46706-w

Experimental method

ELECTRON MICROSCOPY (3.41 Å)