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- EMDB-19440: Cryo-EM structure of human NTCP-Bulevirtide complex -

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Basic information

Entry
Database: EMDB / ID: EMD-19440
TitleCryo-EM structure of human NTCP-Bulevirtide complex
Map data
Sample
  • Complex: Structure of Bulevirtide-bound human NTCP in complex with Fab and nanobody
    • Protein or peptide: Sodium/bile acid cotransporter
    • Protein or peptide: Heavy chain of Fab3
    • Protein or peptide: Light chain of Fab3
    • Protein or peptide: Fab-specific nanobody
    • Protein or peptide: Polymerase
  • Ligand: N-tetradecanoylglycine
  • Ligand: water
KeywordsHepatitis B/D virus receptor / bile salt transporter / drugs / inhibitor / TRANSPORT PROTEIN
Function / homology
Function and homology information


bile acid:sodium symporter activity / membrane fusion involved in viral entry into host cell / bile acid transmembrane transporter activity / bile acid and bile salt transport / Recycling of bile acids and salts / response to nutrient levels / response to estrogen / cellular response to xenobiotic stimulus / virus receptor activity / response to ethanol ...bile acid:sodium symporter activity / membrane fusion involved in viral entry into host cell / bile acid transmembrane transporter activity / bile acid and bile salt transport / Recycling of bile acids and salts / response to nutrient levels / response to estrogen / cellular response to xenobiotic stimulus / virus receptor activity / response to ethanol / basolateral plasma membrane / symbiont entry into host cell / virion attachment to host cell / virion membrane / plasma membrane
Similarity search - Function
Large envelope protein S / Major surface antigen from hepadnavirus / 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
Polymerase / Hepatic sodium/bile acid cotransporter
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama) / hepatitis B virus genotype C
Methodsingle particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsLiu H / Zakrzewicz D / Nosol K / Irobalieva RN / Mukherjee S / Bang-Soerensen R / Goldmann N / Kunz S / Rossi L / Kossiakoff AA ...Liu H / Zakrzewicz D / Nosol K / Irobalieva RN / Mukherjee S / Bang-Soerensen R / Goldmann N / Kunz S / Rossi L / Kossiakoff AA / Urban S / Glebe D / Geyer J / Locher KP
Funding support Switzerland, Germany, United States, 4 items
OrganizationGrant numberCountry
Swiss National Science Foundation214834 Switzerland
Swiss National Science Foundation189111 Switzerland
German Research Foundation (DFG)197785619 Germany
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM117372 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP.
Authors: Hongtao Liu / Dariusz Zakrzewicz / Kamil Nosol / Rossitza N Irobalieva / Somnath Mukherjee / Rose Bang-Sørensen / Nora Goldmann / Sebastian Kunz / Lorenzo Rossi / Anthony A Kossiakoff / ...Authors: Hongtao Liu / Dariusz Zakrzewicz / Kamil Nosol / Rossitza N Irobalieva / Somnath Mukherjee / Rose Bang-Sørensen / Nora Goldmann / Sebastian Kunz / Lorenzo Rossi / Anthony A Kossiakoff / Stephan Urban / Dieter Glebe / Joachim Geyer / Kaspar P Locher /
Abstract: Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate co-transporting polypeptide (NTCP). ...Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.
History
DepositionJan 18, 2024-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19440.png

Downloads & links

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Map

FileDownload / File: emd_19440.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 384 pix.
= 249.6 Å		0.65 Å/pix.
x 384 pix.
= 249.6 Å		0.65 Å/pix.
x 384 pix.
= 249.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.65 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.428
Minimum - Maximum-2.2951088 - 2.940475
Average (Standard dev.)0.0002254033 (±0.05943929)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.59999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19440_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_19440_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19440_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of Bulevirtide-bound human NTCP in complex with Fab and...

EntireName: Structure of Bulevirtide-bound human NTCP in complex with Fab and nanobody
Components
  • Complex: Structure of Bulevirtide-bound human NTCP in complex with Fab and nanobody
    • Protein or peptide: Sodium/bile acid cotransporter
    • Protein or peptide: Heavy chain of Fab3
    • Protein or peptide: Light chain of Fab3
    • Protein or peptide: Fab-specific nanobody
    • Protein or peptide: Polymerase
  • Ligand: N-tetradecanoylglycine
  • Ligand: water

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Supramolecule #1: Structure of Bulevirtide-bound human NTCP in complex with Fab and...

SupramoleculeName: Structure of Bulevirtide-bound human NTCP in complex with Fab and nanobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 110 KDa

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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: 38.149949 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEAHNASAPF NFTLPPNFGK RPTDLALSVI LVFMLFFIML SLGCTMEFSK IKAHLWKPKG LAIALVAQYG IMPLTAFVLG KVFRLKNIE ALAILVCGCS PGGNLSNVFS LAMKGDMNLS IVMTTCSTFC ALGMMPLLLY IYSRGIYDGD LKDKVPYKGI V ISLVLVLI ...String:
MEAHNASAPF NFTLPPNFGK RPTDLALSVI LVFMLFFIML SLGCTMEFSK IKAHLWKPKG LAIALVAQYG IMPLTAFVLG KVFRLKNIE ALAILVCGCS PGGNLSNVFS LAMKGDMNLS IVMTTCSTFC ALGMMPLLLY IYSRGIYDGD LKDKVPYKGI V ISLVLVLI PCTIGIVLKS KRPQYMRYVI KGGMIIILLC SVAVTVLSAI NVGKSIMFAM TPLLIATSSL MPFIGFLLGY VL SALFCLN GRCRRTVSME TGCQNVQLCS TILNVAFPPE VIGPLFFFPL LYMIFQLGEG LLLIAIFWCY EKFKTPKDKT KMI YTAATT EETIPGALGN GTYKGEDCSP CTA

UniProtKB: Hepatic sodium/bile acid cotransporter

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Macromolecule #2: Heavy chain of Fab3

MacromoleculeName: Heavy chain of Fab3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.197955 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVSSSYIHWV RQAPGKGLEW VASISPYYSY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYQYDYYYS YYAGLDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVSSSYIHWV RQAPGKGLEW VASISPYYSY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYQYDYYYS YYAGLDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHT

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Macromolecule #3: Light chain of Fab3

MacromoleculeName: Light chain of Fab3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.481094 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYRYSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYRYSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: Fab-specific nanobody

MacromoleculeName: Fab-specific nanobody / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 13.118386 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VQLQESGGGL VQPGGSLRLS CAASGRTISR YAMSWFRQAP GKEREFVAVA RRSGDGAFYA DSVQGRFTVS RDDAKNTVYL QMNSLKPED TAVYYCAIDS DTFYSGSYDY WGQGTQVTVS S

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Macromolecule #5: Polymerase

MacromoleculeName: Polymerase / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: hepatitis B virus genotype C
Molecular weightTheoretical: 5.136473 KDa
SequenceString:
TNLSVPNPLG FFPDHQLDPA FGANSNNPDW DFNPNKDHWP EANKVG

UniProtKB: Polymerase

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Macromolecule #6: N-tetradecanoylglycine

MacromoleculeName: N-tetradecanoylglycine / type: ligand / ID: 6 / Number of copies: 1 / Formula: BJU
Molecular weightTheoretical: 285.422 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7zyi

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 128700
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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