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Structural basis of sodium-dependent bile salt uptake into the liver.
Goutam, Kapil; Ielasi, Francesco S; Pardon, Els; Steyaert, Jan; Reyes, Nicolas.
Afiliação
  • Goutam K; Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Pessac, France.
  • Ielasi FS; Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France.
  • Pardon E; Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France.
  • Steyaert J; Structural Biology Brussels, Vrije Universiteit Brussel, VUB, Brussels, Belgium.
  • Reyes N; VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
Nature ; 606(7916): 1015-1020, 2022 06.
Article em En | MEDLINE | ID: mdl-35545671
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sódio / Ácidos e Sais Biliares / Microscopia Crioeletrônica / Transportadores de Ânions Orgânicos Dependentes de Sódio / Simportadores / Fígado Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sódio / Ácidos e Sais Biliares / Microscopia Crioeletrônica / Transportadores de Ânions Orgânicos Dependentes de Sódio / Simportadores / Fígado Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article