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- EMDB-31526: human NTCP in complex with YN69083 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-31526
Titlehuman NTCP in complex with YN69083 FabSodium/bile acid cotransporter
Map datapostprocess map
Sample
  • Organelle or cellular component: human NTCP in complex with YN69083Sodium/bile acid cotransporter
    • Complex: NTCPSodium/bile acid cotransporter
      • Protein or peptide: Sodium/bile acid cotransporter
    • Complex: Fab Light chain,Fab Heavy chain
      • Protein or peptide: Fab Light chainFragment antigen-binding
      • Protein or peptide: Fab Heavy chainFragment antigen-binding
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsPark JH / Iwamoto M / Yun JH / Uchikubo-Kamo T / Son D / Jin Z / Yoshida H / Ohki M / Ishimoto N / Mizutani K ...Park JH / Iwamoto M / Yun JH / 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 JRH / Nishizawa T / Lee W / Park SY
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, 2021-
Header (metadata) releaseMay 25, 2022-
Map releaseMay 25, 2022-
UpdateJul 13, 2022-
Current statusJul 13, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_31526.png

Downloads & links

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Map

FileDownload / File: emd_31526.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpostprocess map
Voxel sizeX=Y=Z: 0.829 Å
Density
Contour LevelBy AUTHOR: 0.017
Minimum - Maximum-0.114744335 - 0.18000707
Average (Standard dev.)0.0002782215 (±0.0032938956)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 215.54 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_31526_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap1

Fileemd_31526_half_map_1.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap2

Fileemd_31526_half_map_2.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human NTCP in complex with YN69083

EntireName: human NTCP in complex with YN69083Sodium/bile acid cotransporter
Components
  • Organelle or cellular component: human NTCP in complex with YN69083Sodium/bile acid cotransporter
    • Complex: NTCPSodium/bile acid cotransporter
      • Protein or peptide: Sodium/bile acid cotransporter
    • Complex: Fab Light chain,Fab Heavy chain
      • Protein or peptide: Fab Light chainFragment antigen-binding
      • Protein or peptide: Fab Heavy chainFragment antigen-binding

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Supramolecule #1: human NTCP in complex with YN69083

SupramoleculeName: human NTCP in complex with YN69083 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 89 KDa

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Supramolecule #2: NTCP

SupramoleculeName: NTCP / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Fab Light chain,Fab Heavy chain

SupramoleculeName: Fab Light chain,Fab Heavy chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mus musculus (house mouse)

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Macromolecule #1: Sodium/bile acid cotransporter

MacromoleculeName: Sodium/bile acid cotransporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.529355 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPGAPMEAHN ASAPFNFTLP PNFGKRPTDL ALSVILVFML FFIMLSLGCT MEFSKIKAHL WKPKGLAIAL VAQYGIMPLT AFVLGKVFR LKNIEALAIL VCGCSPGGNL SNVFSLAMKG DMNLSIVMTT CSTFCALGMM PLLLYIYSRG IYDGDLKDKV P YKGIVISL ...String:
GPGAPMEAHN ASAPFNFTLP PNFGKRPTDL ALSVILVFML FFIMLSLGCT MEFSKIKAHL WKPKGLAIAL VAQYGIMPLT AFVLGKVFR LKNIEALAIL VCGCSPGGNL SNVFSLAMKG DMNLSIVMTT CSTFCALGMM PLLLYIYSRG IYDGDLKDKV P YKGIVISL VLVLIPCTIG IVLKSKRPQY MRYVIKGGMI IILLCSVAVT VLSAINVGKS IMFAMTPLLI ATSSLMPFIG FL LGYVLSA LFCLNGRCRR TVSMETGCQN VQLCSTILNV AFPPEVIGPL FFFPLLYMIF QLGEGLLLIA IFWCYEKFKT PKD KTKMIY TAATTEETIP GALGNGTYKG EDCSPCTA

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Macromolecule #2: Fab Light chain

MacromoleculeName: Fab Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.3829 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: DIVMTQSPAI MSASPGQKVT ITCSASSSVN YMHWYQQKLG SSPKLWIYDT SKLALGVPAR FSGSGSGTSY SLTISSMEAE DAASYFCHQ WSSYPRTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String:
DIVMTQSPAI MSASPGQKVT ITCSASSSVN YMHWYQQKLG SSPKLWIYDT SKLALGVPAR FSGSGSGTSY SLTISSMEAE DAASYFCHQ WSSYPRTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC

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Macromolecule #3: Fab Heavy chain

MacromoleculeName: Fab Heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.418123 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: EVQLQQPGAE LVKPGASVKL SCKTSGYTFT NYWMKWVKQR PGQGLEWIGE INPSNGGTNY NGKFKSKASL TVDKSSSTAY MQLSSLTSE DSAVYYCTIL VYDAYYVFAM DYWGLGTSVT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC LVKGYFPEPV T VTWNSGSL ...String:
EVQLQQPGAE LVKPGASVKL SCKTSGYTFT NYWMKWVKQR PGQGLEWIGE INPSNGGTNY NGKFKSKASL TVDKSSSTAY MQLSSLTSE DSAVYYCTIL VYDAYYVFAM DYWGLGTSVT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC LVKGYFPEPV T VTWNSGSL SSGVHTFPAV LQSDLYTLSS SVTVPSSTWP SETVTCNVAH PASSTKVDKK IVPRDCGCKP CICTVPEVSS VF IFPPKPK DVLTITLT

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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

Concentration6 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClSodium chlorideSodium chloride
0.005 %LMNGLauryl maltose-neopentyl glycol
GridModel: Quantifoil R0.6/1 / Material: COPPER/RHODIUM / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 12.0 nm
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 302 K / Instrument: FEI VITROBOT MARK IV

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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 / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: RELION (ver. 3.1.2)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.2)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 688462
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4n7x


Chain - Chain ID: A
Output model

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

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