7pqq | pdb_00007pqq
Structure of thermostabilised human NTCP in complex with Megabody 91
Structural highlights
DiseaseNTCP_HUMAN Familial hypercholanemia. The disease is caused by variants affecting the gene represented in this entry. FunctionNTCP_HUMAN As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It is strictly dependent on the extracellular presence of sodium (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate (PubMed:14660639, PubMed:34060352). Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321).[1] [2] [3] [4] [5] (Microbial infection) Acts as a receptor for hepatitis B virus.[6] Publication Abstract from PubMedThe 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. Structural basis of sodium-dependent bile salt uptake into the liver.,Goutam K, Ielasi FS, Pardon E, Steyaert J, Reyes N Nature. 2022 Jun;606(7916):1015-1020. doi: 10.1038/s41586-022-04723-z. Epub 2022 , May 11. PMID:35545671[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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