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

Article

关键词: MULTIPLE SEQUENCE ALIGNMENT;    B-VIRUS ATTACHMENT;    HEPATITIS-B;    ACID UPTAKE;    TAUROCHOLATE;    TRANSPORT;    INFECTION;    POLYPEPTIDE;    INHIBITION;    EXPRESSION;   

DOI  :  10.1038/s41586-022-04723-z

来源: SCIE

【 摘 要 】

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) isthe 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(1). 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 itstransport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves asthe transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside ofthe cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition ofthe HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity ofthe viruses for open-to-outside over inward-facing conformations ofthe 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.

【 授权许可】

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