Abstract
Around 250 million people are infected with hepatitis B virus (HBV) worldwide1, and 15 million may also carry the satellite virus hepatitis D virus (HDV), which confers even greater risk of severe liver disease2. The HBV receptor has been identified as sodium taurocholate co-transporting polypeptide (NTCP), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large protein3. Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria4,5, and these models are believed to resemble closely both NTCP and ASBT. Here we have used cryo-electron microscopy to solve the structure of NTCP bound to an antibody, clearly showing that the transporter has no equivalent of the first transmembrane helix found in other SLC10 proteins, and that the N terminus is exposed on the extracellular face. Comparison of our structure with those of related proteins indicates a common mechanism of bile acid transport, but the NTCP structure displays an additional pocket formed by residues that are known to interact with preS1, presenting new opportunities for structure-based drug design.
| Original language | English |
|---|---|
| Pages (from-to) | 1027-1031 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 606 |
| Issue number | 7916 |
| DOIs | |
| Publication status | Published - 2022 Jun 30 |
Bibliographical note
Funding Information:The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research (Yokohama). We thank C. Kobayashi and J. Mifune for providing cDNA plasmids for NTCP mutants; F. Kawai and K. Gomi for help with the expression check for NTCP; R. Akihide and K. Miyakawa for supplying the antibody; and T. Miyamura and F. Chisari for providing HepG2 and Huh7 cells, respectively. This work was supported by Japan Agency for Medical Research and Development, AMED under grant numbers JP21fk0310103 (to S.-Y.P., T.W., K.W. and M.M.) and by JSPS/MEXT KAKENHI grant (JP19H05779 and JP21H02449 to S.-Y.P.). This work was also supported by National Research Foundation of Korea (grant No. NRF-2019M3E5D6063903, 2017M3A9F6029753, 2018K2A9A2A06024227 to W.L.). This work was partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED under grant number JP18am0101076 (to S.-Y.P.), JP20am0101082 (to M.S.) and Takeda Science Foundation (to S.-Y.P.). J.R.H.T. thanks OpenEye Scientific Software for support.
Funding Information:
The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research (Yokohama). We thank C. Kobayashi and J. Mifune for providing cDNA plasmids for NTCP mutants; F. Kawai and K. Gomi for help with the expression check for NTCP; R. Akihide and K. Miyakawa for supplying the antibody; and T. Miyamura and F. Chisari for providing HepG2 and Huh7 cells, respectively. This work was supported by Japan Agency for Medical Research and Development, AMED under grant numbers JP21fk0310103 (to S.-Y.P., T.W., K.W. and M.M.) and by JSPS/MEXT KAKENHI grant (JP19H05779 and JP21H02449 to S.-Y.P.). This work was also supported by National Research Foundation of Korea (grant No. NRF-2019M3E5D6063903, 2017M3A9F6029753, 2018K2A9A2A06024227 to W.L.). This work was partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED under grant number JP18am0101076 (to S.-Y.P.), JP20am0101082 (to M.S.) and Takeda Science Foundation (to S.-Y.P.). J.R.H.T. thanks OpenEye Scientific Software for support.
Publisher Copyright:
© 2022, The Author(s).
All Science Journal Classification (ASJC) codes
- General
