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- EMDB-13593: Structure of thermostabilised human NTCP in complex with nanobody 87 -

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Basic information

Entry
Database: EMDB / ID: EMD-13593
TitleStructure of thermostabilised human NTCP in complex with nanobody 87
Map data
Sample
  • Complex: Human NTCP in complex with nanobody 87Sodium/bile acid cotransporter
    • Protein or peptide: Nanobody 87Single-domain antibody
    • Protein or peptide: Sodium/bile acid cotransporter
Function / homology
Function and homology information


bile acid:sodium symporter activity / regulation of bile acid secretion / bile acid and bile salt transport / bile acid signaling pathway / Recycling of bile acids and salts / response to nutrient levels / response to organic cyclic compound / response to estrogen / cellular response to xenobiotic stimulus / virus receptor activity ...bile acid:sodium symporter activity / regulation of bile acid secretion / bile acid and bile salt transport / bile acid signaling pathway / Recycling of bile acids and salts / response to nutrient levels / response to organic cyclic compound / response to estrogen / cellular response to xenobiotic stimulus / virus receptor activity / basolateral plasma membrane / response to ethanol / plasma membrane
Similarity search - Function
Bile acid:sodium symporter/arsenical resistance protein Acr3 / Bile acid:sodium symporter / Sodium Bile acid symporter family / Sodium/solute symporter superfamily
Similarity search - Domain/homology
Hepatic sodium/bile acid cotransporter
Similarity search - Component
Biological speciesLama glama (llama) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsGoutam K / Reyes N
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)309657European Union
CitationJournal: Nature / Year: 2022
Title: Structural basis of sodium-dependent bile salt uptake into the liver.
Authors: Kapil Goutam / Francesco S Ielasi / Els Pardon / Jan Steyaert / Nicolas Reyes /
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) ...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.
History
DepositionSep 21, 2021-
Header (metadata) releaseMay 18, 2022-
Map releaseMay 18, 2022-
UpdateJul 6, 2022-
Current statusJul 6, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_13593.png

Downloads & links

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Map

FileDownload / File: emd_13593.map.gz / Format: CCP4 / Size: 113.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.008 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.14079145 - 0.9309559
Average (Standard dev.)-0.000117141695 (±0.0077005485)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions310310310
Spacing310310310
CellA=B=C: 312.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Human NTCP in complex with nanobody 87

EntireName: Human NTCP in complex with nanobody 87Sodium/bile acid cotransporter
Components
  • Complex: Human NTCP in complex with nanobody 87Sodium/bile acid cotransporter
    • Protein or peptide: Nanobody 87Single-domain antibody
    • Protein or peptide: Sodium/bile acid cotransporter

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Supramolecule #1: Human NTCP in complex with nanobody 87

SupramoleculeName: Human NTCP in complex with nanobody 87 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Lama glama (llama)

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Macromolecule #1: Nanobody 87

MacromoleculeName: Nanobody 87 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama) / Strain: Lama glama
Molecular weightTheoretical: 14.988481 KDa
Recombinant expressionOrganism: Escherichia coli K-12 (bacteria)
SequenceString:
QVQLVESGGG LVQAGGSLRL SCAVSGRTTA NYNMGWFRQA PGKEREFVAG IKWSSGSTYV ADSAKGRFTI SRDNAKNSVY LQMDSLKPE DTALYYCAAN YYGVSWFLIS PSSYDYWGQG TQVTVSSHHH HHHEPEA

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Macromolecule #2: Sodium/bile acid cotransporter

MacromoleculeName: Sodium/bile acid cotransporter / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.652391 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAHTASAPFT FTLPPNFGKR PTDLALSVIL VVMLFIIMLS LGCTMEFSKI KAHLWKPKGL AIALVAQYGI MPLTAFVLGK VFRLNNIEA LAILICGCSP GGNLSNIFSL AMKGDMNLSI VMTTCSTFLA LGMMPLLLYI YSRGIYDGDL KDKVPYKGIV I SLVLVLIP ...String:
MAHTASAPFT FTLPPNFGKR PTDLALSVIL VVMLFIIMLS LGCTMEFSKI KAHLWKPKGL AIALVAQYGI MPLTAFVLGK VFRLNNIEA LAILICGCSP GGNLSNIFSL AMKGDMNLSI VMTTCSTFLA LGMMPLLLYI YSRGIYDGDL KDKVPYKGIV I SLVLVLIP CTIGIVLKSK RPQYMRYVIK GGMIIILLCS VAVTVLSAIN VGKSIMFAMT PHLIATSSLM PFIGFLLGYV LS ALFCLNG RCRRTVSMET GCQNVQLCST ILNVAFPPEV IGPLFFFPLL YMIFQLGEGL LLIAIFWCYE KFKTPKDKTK MIY TAATTE ELEVLFQ

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: The initial model for Nanobody was created using I-TASSER server. Transporter was modelled using NTCP-Nb91 high-resolution structure as the initial model.
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 61053

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