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- PDB-7vad: Cryo-EM structure of human NTCP complexed with YN69202Fab -

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Basic information

Entry
Database: PDB / ID: 7vad
TitleCryo-EM structure of human NTCP complexed with YN69202Fab
Components
  • Fab heavy chain from antibody IgG clone number YN69202
  • Fab light chain from antibody IgG clone number YN69202
  • Sodium/bile acid cotransporter
KeywordsTRANSPORT PROTEIN / Hepatitis B virus (HBV) / host entry receptor / bile acid transporter / taurocholate / Na+-coupled symporter
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 speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsAsami, J. / Shimizu, T. / Ohto, U.
Funding support Japan, 2items
OrganizationGrant numberCountry
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H03164 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)19H00976 Japan
CitationJournal: Nature / Year: 2022
Title: Structure of the bile acid transporter and HBV receptor NTCP.
Authors: Jinta Asami / Kanako Terakado Kimura / Yoko Fujita-Fujiharu / Hanako Ishida / Zhikuan Zhang / Yayoi Nomura / Kehong Liu / Tomoko Uemura / Yumi Sato / Masatsugu Ono / Masaki Yamamoto / ...Authors: Jinta Asami / Kanako Terakado Kimura / Yoko Fujita-Fujiharu / Hanako Ishida / Zhikuan Zhang / Yayoi Nomura / Kehong Liu / Tomoko Uemura / Yumi Sato / Masatsugu Ono / Masaki Yamamoto / Takeshi Noda / Hideki Shigematsu / David Drew / So Iwata / Toshiyuki Shimizu / Norimichi Nomura / Umeharu Ohto /
Abstract: Chronic infection with hepatitis B virus (HBV) affects more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma, and results in an estimated 820,000 deaths ...Chronic infection with hepatitis B virus (HBV) affects more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma, and results in an estimated 820,000 deaths annually. For HBV infection to be established, a molecular interaction is required between the large glycoproteins of the virus envelope (known as LHBs) and the host entry receptor sodium taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from the blood to hepatocytes. However, the molecular basis for the virus-transporter interaction is poorly understood. Here we report the cryo-electron microscopy structures of human, bovine and rat NTCPs in the apo state, which reveal the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-electron microscopy structure of human NTCP in the presence of the myristoylated preS1 domain of LHBs, together with mutation and transport assays, suggest a binding mode in which preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Our preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Together, our findings provide a structural framework for HBV recognition and a mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.
History
DepositionAug 29, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 25, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Source and taxonomy
Category: citation / citation_author ...citation / citation_author / em_entity_assembly_naturalsource / entity_src_gen
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID ..._citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name / _em_entity_assembly_naturalsource.ncbi_tax_id / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id
Revision 1.2Jul 6, 2022Group: Database references / Category: citation / Item: _citation.title
Revision 1.3Jul 13, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium/bile acid cotransporter
H: Fab heavy chain from antibody IgG clone number YN69202
L: Fab light chain from antibody IgG clone number YN69202


Theoretical massNumber of molelcules
Total (without water)89,0413
Polymers89,0413
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5650 Å2
ΔGint-31 kcal/mol
Surface area36640 Å2

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Components

#1: Protein Sodium/bile acid cotransporter / / Cell growth-inhibiting gene 29 protein / Na(+)/bile acid cotransporter / Na(+)/taurocholate ...Cell growth-inhibiting gene 29 protein / Na(+)/bile acid cotransporter / Na(+)/taurocholate transport protein / Sodium/taurocholate cotransporting polypeptide / Solute carrier family 10 member 1


Mass: 38141.832 Da / Num. of mol.: 1 / Mutation: Q261A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTCP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14973
#2: Antibody Fab heavy chain from antibody IgG clone number YN69202


Mass: 26574.695 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Antibody Fab light chain from antibody IgG clone number YN69202


Mass: 24323.990 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Complex of NTCP and FabCOMPLEXall0MULTIPLE SOURCES
2NTCP:COMPLEX#11RECOMBINANT
3FabFragment antigen-bindingCOMPLEX#2-#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Mus musculus (house mouse)11060
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Spodoptera frugiperda (fall armyworm)7108ExpiSf9
32Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
Details: 25 mM Hepes-NaOH, pH 7.5, 0.15 M NaCl, and 0.01% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 61 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103174 / Symmetry type: POINT

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