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- PDB-8rqf: Cryo-EM structure of human NTCP-Bulevirtide complex -

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Basic information

Entry
Database: PDB / ID: 8rqf
TitleCryo-EM structure of human NTCP-Bulevirtide complex
Components
  • Fab-specific nanobody
  • Heavy chain of Fab3
  • Light chain of Fab3
  • Polymerase
  • Sodium/bile acid cotransporter
KeywordsTRANSPORT PROTEIN / Hepatitis B/D virus receptor / bile salt transporter / drugs / inhibitor
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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsLiu, H. / Zakrzewicz, D. / Nosol, K. / Irobalieva, R.N. / Mukherjee, S. / Bang-Soerensen, R. / Goldmann, N. / Kunz, S. / Rossi, L. / Kossiakoff, A.A. ...Liu, H. / Zakrzewicz, D. / Nosol, K. / Irobalieva, R.N. / Mukherjee, S. / Bang-Soerensen, R. / Goldmann, N. / Kunz, S. / Rossi, L. / Kossiakoff, A.A. / Urban, S. / Glebe, D. / Geyer, J. / Locher, K.P.
Funding support Switzerland, Germany, United States, 4items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Oct 23, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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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: Heavy chain of Fab3
L: Light chain of Fab3
K: Fab-specific nanobody
B: Polymerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,3696
Polymers105,0845
Non-polymers2851
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Antibody , 3 types, 3 molecules HLK

#2: Antibody Heavy chain of Fab3


Mass: 25197.955 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Light chain of Fab3


Mass: 23481.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody Fab-specific nanobody


Mass: 13118.386 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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: 38149.949 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: Homo sapiens (human) / References: UniProt: Q14973
#5: Protein/peptide Polymerase


Mass: 5136.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) hepatitis B virus genotype C / References: UniProt: A0A515J2X9

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-BJU / N-tetradecanoylglycine


Mass: 285.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H31NO3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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

ComponentName: Structure of Bulevirtide-bound human NTCP in complex with Fab and nanobody
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.11 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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 FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (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: 128700 / Symmetry type: POINT

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