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Structural basis of sodium-dependent bile salt uptake into the liver

The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs(1). Human Na(+)–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of huma...

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Autores principales: Goutam, Kapil, Ielasi, Francesco S., Pardon, Els, Steyaert, Jan, Reyes, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242856/
https://www.ncbi.nlm.nih.gov/pubmed/35545671
http://dx.doi.org/10.1038/s41586-022-04723-z
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author Goutam, Kapil
Ielasi, Francesco S.
Pardon, Els
Steyaert, Jan
Reyes, Nicolas
author_facet Goutam, Kapil
Ielasi, Francesco S.
Pardon, Els
Steyaert, Jan
Reyes, Nicolas
author_sort Goutam, Kapil
collection PubMed
description The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs(1). Human Na(+)–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses(2,3) (HBV/HDV), and has emerged as an important target for antiviral drugs(4). However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP ‘gated-pore’ transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP.
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spelling pubmed-92428562022-07-01 Structural basis of sodium-dependent bile salt uptake into the liver Goutam, Kapil Ielasi, Francesco S. Pardon, Els Steyaert, Jan Reyes, Nicolas Nature Article The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs(1). Human Na(+)–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses(2,3) (HBV/HDV), and has emerged as an important target for antiviral drugs(4). However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP ‘gated-pore’ transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP. Nature Publishing Group UK 2022-05-11 2022 /pmc/articles/PMC9242856/ /pubmed/35545671 http://dx.doi.org/10.1038/s41586-022-04723-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Goutam, Kapil
Ielasi, Francesco S.
Pardon, Els
Steyaert, Jan
Reyes, Nicolas
Structural basis of sodium-dependent bile salt uptake into the liver
title Structural basis of sodium-dependent bile salt uptake into the liver
title_full Structural basis of sodium-dependent bile salt uptake into the liver
title_fullStr Structural basis of sodium-dependent bile salt uptake into the liver
title_full_unstemmed Structural basis of sodium-dependent bile salt uptake into the liver
title_short Structural basis of sodium-dependent bile salt uptake into the liver
title_sort structural basis of sodium-dependent bile salt uptake into the liver
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242856/
https://www.ncbi.nlm.nih.gov/pubmed/35545671
http://dx.doi.org/10.1038/s41586-022-04723-z
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