한빛사논문
- 조회706
Jae-Hyun Park1, Masashi Iwamoto2, Ji-Hye Yun3,4, Tomomi Uchikubo-Kamo5, Donghwan Son3, Zeyu Jin1,3, Hisashi Yoshida1, Mio Ohki1, Naito Ishimoto1, Kenji Mizutani1, Mizuki Oshima2,6, Masamichi Muramatsu2, Takaji Wakita2, Mikako Shirouzu5, Kehong Liu7, Tomoko Uemura7, Norimichi Nomura7, So Iwata7,8, Koichi Watashi2,6,9, Jeremy R. H. Tame1, Tomohiro Nishizawa10, Weontae Lee3,4*, Sam-Yong Park1*
1Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama 230-0045, Japan.
2Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku15 ku, Tokyo 162-8640, Japan.
3Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
4PCG-Biotech, Ltd, Yonsei Engineering Research Park 114A, Yonsei-Ro 50, Seoul 03722, South Korea.
5Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
6Department of Biological Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan
7Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
8RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, Japan.
9Research Center for Drug and Vaccine Development, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
10Laboratory of Biomembrane Dynamics, Graduate School of Medical Life Science, Yokohama City University, Tsurumi, Yokohama 230-0045, Japan.
*Corresponding author
Abstract
Roughly 250 million people are infected with hepatitis B virus (HBV) worldwide1, and perhaps 15 million also carry the satellite virus HDV, which confers even greater risk of severe liver disease2. Almost ten years ago the HBV receptor was identified as NTCP (sodium taurocholate co-transporting polypeptide), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large (L) 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 with ten transmembrane helices are believed to resemble strongly both NTCP and ASBT. Using cryo-electron microscopy we have solved the structure of NTCP bound to an antibody, clearly showing the transporter has no equivalent to the first transmembrane helix of other SLC10 models, leaving the N-terminus exposed on the extracellular face. Comparison of the different structures indicates a common mechanism of bile acid transport, but the NTCP structure also displays a pocket formed by residues known to interact with preS1, presenting new and enticing opportunities for structure-based drug design.
논문정보
- Research article
- 2022년 05월 (BRIC 등록일 2022-05-23)
- 국내(교신)+국외 연구진
- 생명과학 > 생화학
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