7PQQ

Structure of thermostabilised human NTCP in complex with Megabody 91

Summary for 7PQQ

• Entry DOI: 10.2210/pdb7pqq/pdb
• EMDB information: 13596
• Descriptor: Sodium/bile acid cotransporter, Anti-RON nanobody,Megabody 91,Glucosidase YgjK (2 entities in total)
• Functional Keywords: bile acid transporter, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 138235.42

Authors

Goutam, K.,Reyes, N. (deposition date: 2021-09-18, release date: 2022-05-18, Last modification date: 2022-07-06)

Primary citation

Goutam, K.,Ielasi, F.S.,Pardon, E.,Steyaert, J.,Reyes, N.
Structural basis of sodium-dependent bile salt uptake into the liver.
Nature, 606:1015-1020, 2022

PubMed Abstract: The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs. 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 (HBV/HDV), and has emerged as an important target for antiviral drugs. 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.

PubMed: 35545671
DOI: 10.1038/s41586-022-04723-z

Experimental method

ELECTRON MICROSCOPY (3.3 Å)