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- PDB-7dwt: Cryo-EM structure of Dengue virus serotype 1 strain WestPac 74 in... -

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Basic information

Entry
Database: PDB / ID: 7dwt
TitleCryo-EM structure of Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab at 37 deg C (Class 1 particle)
Components
  • Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
  • Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
  • envelope proteinViral envelope
KeywordsVIRUS/IMMUNE SYSTEM / dengue virus / human antibody / dengue-Fab structure / VIRUS / VIRUS-IMMUNE SYSTEM complex
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / viral capsid / : / nucleoside-triphosphate phosphatase / double-stranded RNA binding / protein complex oligomerization ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / viral capsid / : / nucleoside-triphosphate phosphatase / double-stranded RNA binding / protein complex oligomerization / monoatomic ion channel activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
: / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / : / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A ...: / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / : / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesDengue virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 19 Å
AuthorsFibriansah, G. / Ng, T.S. / Kostyuchenko, V.A. / Shi, J. / Lok, S.M.
Funding support Singapore, United States, 3items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF-NRFI2016-01 Singapore
National Research Foundation (NRF, Singapore)NRF2017NRF-CRP001-027 Singapore
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U54 AI 057157 United States
CitationJournal: PLoS Pathog / Year: 2021
Title: Antibody affinity versus dengue morphology influences neutralization.
Authors: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter ...Authors: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter J Bond / James E Crowe / Shee-Mei Lok /
Abstract: Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the ...Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes. We mapped the 1C19 epitope to E protein domain II by hydrogen deuterium exchange mass spectrometry, cryoEM and molecular dynamics simulations, revealing that this epitope is likely partially hidden on the virus surface. We showed the antibody has high affinity for binding to recombinant DENV1 E proteins compared to those of DENV2, consistent with its strong neutralizing activities for all DENV1 strains tested regardless of their morphologies. This finding suggests that the antibody could out-compete E-to-E interaction for binding to its epitope. In contrast, for DENV2, HMAb 1C19 can only neutralize when the epitope becomes exposed on the bumpy-surfaced particle. Although HMAb 1C19 is not a suitable therapeutic candidate, this study with HMAb 1C19 shows the importance of choosing a high-affinity antibody that could neutralize diverse dengue virus morphologies for therapeutic purposes.
History
DepositionJan 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author
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 / _citation_author.name
Revision 1.2Mar 27, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type

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Structure visualization

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  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
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Structure viewerMolecule:
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Assembly

Deposited unit
A: envelope protein
B: envelope protein
C: envelope protein
H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain


Theoretical massNumber of molelcules
Total (without water)186,4855
Polymers186,4855
Non-polymers00
Water0
1
A: envelope protein
B: envelope protein
C: envelope protein
H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
x 60


Theoretical massNumber of molelcules
Total (without water)11,189,106300
Polymers11,189,106300
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: envelope protein
B: envelope protein
C: envelope protein
H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
x 5


  • icosahedral pentamer
  • 932 kDa, 25 polymers
Theoretical massNumber of molelcules
Total (without water)932,42525
Polymers932,42525
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: envelope protein
B: envelope protein
C: envelope protein
H: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
L: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
x 6


  • icosahedral 23 hexamer
  • 1.12 MDa, 30 polymers
Theoretical massNumber of molelcules
Total (without water)1,118,91130
Polymers1,118,91130
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein envelope protein / Viral envelope / Coordinate model: Cα atoms only


Mass: 53910.871 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Dengue virus 1 / Strain: WestPac 74 / References: UniProt: P17763*PLUS
#2: Antibody Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain / Coordinate model: Cα atoms only


Mass: 13167.631 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#3: Antibody Anti-dengue virus human monoclonal antibody 1C19 Fab light chain / Coordinate model: Cα atoms only


Mass: 11584.849 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)

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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
IDNameTypeDetailsEntity IDParent-IDSource
1Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 FabCOMPLEXDengue virus serotype 1 strain WestPac 74 was grown in Aedes albopictus C6/36 cells.all0MULTIPLE SOURCES
2Dengue virus 1COMPLEXDengue virus serotype 1 strain WestPac 74#11NATURAL
3antibody 1C19 FabCOMPLEXantibody 1C19 Fab#2-#31NATURAL
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
21Dengue virus 111053Western Pacific 74
32Homo sapiens (human)9606
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 8
Details: NTE buffer (12 mM Tris-HCl pH 8.0, 120 mM NaCl and 1 mM EDTA)
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: The purified virus was incubated with Fab 1C19 at 37 deg C for 30 min with a molar ratio of one Fab for every E-protein and followed by incubation at 4 deg C for 2 h.
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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 18 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

EM software
IDNameCategoryDetails
1EMAN2particle selectione2boxer.py
4EMANCTF correction
7Omodel fitting
10MPSAinitial Euler assignment
11MPSAfinal Euler assignment
13MPSA3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4301
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 19 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 1116 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
14CCT

4cct

14CCT1PDBexperimental model
24HIE

4hie

14HIE2PDBexperimental model
34KQ3

4kq3

14KQ33PDBexperimental model

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