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- PDB-7fci: human NTCP in complex with YN69083 Fab -

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Basic information

Entry
Database: PDB / ID: 7fci
Titlehuman NTCP in complex with YN69083 Fab
Components
  • Fab Heavy chainFragment antigen-binding
  • Fab Light chainFragment antigen-binding
  • Sodium/bile acid cotransporter
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / transporter / TRANSPORT PROTEIN / TRANSPORT PROTEIN-IMMUNE SYSTEM complex
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: 3.3 Å
AuthorsPark, J.H. / Iwamoto, M. / Yun, J.H. / Uchikubo-Kamo, T. / Son, D. / Jin, Z. / Yoshida, H. / Ohki, M. / Ishimoto, N. / Mizutani, K. ...Park, J.H. / Iwamoto, M. / Yun, J.H. / Uchikubo-Kamo, T. / Son, D. / Jin, Z. / Yoshida, H. / Ohki, M. / Ishimoto, N. / Mizutani, K. / Oshima, M. / Muramatsu, M. / Wakita, T. / Shirouzu, M. / Liu, K. / Uemura, T. / Nomura, N. / Iwata, S. / Watashi, K. / Tame, J.R.H. / Nishizawa, T. / Lee, W. / Park, S.Y.
CitationJournal: Nature / Year: 2022
Title: Structural insights into the HBV receptor and bile acid transporter NTCP.
Authors: Jae-Hyun Park / Masashi Iwamoto / Ji-Hye Yun / Tomomi Uchikubo-Kamo / Donghwan Son / Zeyu Jin / Hisashi Yoshida / Mio Ohki / Naito Ishimoto / Kenji Mizutani / Mizuki Oshima / Masamichi ...Authors: Jae-Hyun Park / Masashi Iwamoto / Ji-Hye Yun / Tomomi Uchikubo-Kamo / Donghwan Son / Zeyu Jin / Hisashi Yoshida / Mio Ohki / Naito Ishimoto / Kenji Mizutani / Mizuki Oshima / Masamichi Muramatsu / Takaji Wakita / Mikako Shirouzu / Kehong Liu / Tomoko Uemura / Norimichi Nomura / So Iwata / Koichi Watashi / Jeremy R H Tame / Tomohiro Nishizawa / Weontae Lee / Sam-Yong Park /
Abstract: Around 250 million people are infected with hepatitis B virus (HBV) worldwide, and 15 million may also carry the satellite virus hepatitis D virus (HDV), which confers even greater risk of severe ...Around 250 million people are infected with hepatitis B virus (HBV) worldwide, and 15 million may also carry the satellite virus hepatitis D virus (HDV), which confers even greater risk of severe liver disease. The HBV receptor has been identified as sodium taurocholate co-transporting polypeptide (NTCP), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large protein. Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria, and these models are believed to resemble closely both NTCP and ASBT. Here we have used cryo-electron microscopy to solve the structure of NTCP bound to an antibody, clearly showing that the transporter has no equivalent of the first transmembrane helix found in other SLC10 proteins, and that the N terminus is exposed on the extracellular face. Comparison of our structure with those of related proteins indicates a common mechanism of bile acid transport, but the NTCP structure displays an additional pocket formed by residues that are known to interact with preS1, presenting new opportunities for structure-based drug design.
History
DepositionJul 14, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 25, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 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
L: Fab Light chain
H: Fab Heavy chain


Theoretical massNumber of molelcules
Total (without water)89,3303
Polymers89,3303
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 38529.355 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC10A1, NTCP, GIG29 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14973
#2: Antibody Fab Light chain / Fragment antigen-binding


Mass: 23382.900 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#3: Antibody Fab Heavy chain / Fragment antigen-binding


Mass: 27418.123 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)

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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
1human NTCP in complex with YN69083Sodium/bile acid cotransporterORGANELLE OR CELLULAR COMPONENTall0MULTIPLE SOURCES
2NTCPSodium/bile acid cotransporterCOMPLEX#11RECOMBINANT
3Fab Light chain,Fab Heavy chainCOMPLEX#2-#31RECOMBINANT
Molecular weightValue: 0.089 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMSodium chlorideNaClSodium chloride1
30.005 %Lauryl maltose-neopentyl glycolLMNG1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 302 K

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
4RELION3.1.2CTF correction
7Coot0.9.2model fitting
9PHENIX1.19.2-4158model refinement
10RELION3.1.2initial Euler assignment
11RELION3.1.2final Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 688462 / Symmetry type: POINT
Atomic model buildingPDB-ID: 4N7X

4n7x


Pdb chain-ID: A
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035749
ELECTRON MICROSCOPYf_angle_d0.5817817
ELECTRON MICROSCOPYf_dihedral_angle_d4.829781
ELECTRON MICROSCOPYf_chiral_restr0.04908
ELECTRON MICROSCOPYf_plane_restr0.006965

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