Structural basis of sodium-dependent bile salt uptake into the liver
Kapil Goutam 1 2 , Francesco S Ielasi 2 , Els Pardon 3 4 , Jan Steyaert 3 4 , Nicolas Reyes 5 6
Affiliations
Affiliations
1
Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Pessac, France.
2
Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France.
3
Structural Biology Brussels, Vrije Universiteit Brussel, VUB, Brussels, Belgium.
4
VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
5
Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Pessac, France. [email protected].
6
Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France. [email protected].
PMID: 35545671 DOI: 10.1038/s41586-022-04723-z
Abstract
The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs1. 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 viruses2,3 (HBV/HDV), and has emerged as an important target for antiviral drugs4. 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.