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- PDB-7cth: Cryo-EM structure of dengue virus serotype 2 in complex with the ... -

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Basic information

Entry
Database: PDB / ID: 7cth
TitleCryo-EM structure of dengue virus serotype 2 in complex with the scFv fragment of the broadly neutralizing antibody EDE1 C10
Components
  • (Core proteinCapsid) x 2
  • (Single Chain Variable FragmentSingle-chain variable fragment) x 2
KeywordsVIRUS / Dengue virus / antibody / broadly neutralizing / flavivirus
Function / homology
Function and homology information


flavivirin / suppression by virus of host JAK-STAT cascade via inhibition of STAT2 activity / mRNA (guanine-N7-)-methyltransferase activity / host cell endoplasmic reticulum membrane / viral capsid / mRNA (nucleoside-2'-O-)-methyltransferase activity / double-stranded RNA binding / nucleoside-triphosphate phosphatase / RNA helicase activity / RNA helicase ...flavivirin / suppression by virus of host JAK-STAT cascade via inhibition of STAT2 activity / mRNA (guanine-N7-)-methyltransferase activity / host cell endoplasmic reticulum membrane / viral capsid / mRNA (nucleoside-2'-O-)-methyltransferase activity / double-stranded RNA binding / nucleoside-triphosphate phosphatase / RNA helicase activity / RNA helicase / induction by virus of host autophagy / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / suppression by virus of host type I interferon-mediated signaling pathway / virion attachment to host cell / fusion of virus membrane with host endosome membrane / protein dimerization activity / : / host cell nucleus / serine-type endopeptidase activity / virion membrane / structural molecule activity / integral component of membrane / extracellular region / ATP binding / metal ion binding
Similarity search - Function
Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein M / Envelope glycoprotein M, flavivirus / Genome polyprotein, Flavivirus / Flavivirus capsid protein C / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus NS2B domain profile. / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A ...Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein M / Envelope glycoprotein M, flavivirus / Genome polyprotein, Flavivirus / Flavivirus capsid protein C / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus NS2B domain profile. / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / Flavivirus non-structural protein NS2B / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / 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. / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flaviviral glycoprotein E, central domain, subdomain 2 / Flaviviral glycoprotein E, central domain, subdomain 1 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, central and dimerisation domains / Flavivirus glycoprotein central and dimerisation domain / FtsJ-like methyltransferase / Ribosomal RNA methyltransferase FtsJ domain / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flaviviral glycoprotein E, dimerisation domain / Flavivirus glycoprotein, central and dimerisation domain superfamily / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / Helicase, C-terminal / DEAD-like helicases superfamily / Immunoglobulin E-set / Helicase superfamily 1/2, ATP-binding domain / RdRp of positive ssRNA viruses catalytic domain profile. / RNA-directed RNA polymerase, catalytic domain / S-adenosyl-L-methionine-dependent methyltransferase / Peptidase S1, PA clan, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Core protein / Core protein
Similarity search - Component
Biological speciesDengue virus 2
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang, X. / Sharma, A. / Duquerroy, S. / Zhou, Z.H. / Rey, F.A.
Funding support France, China, 3items
OrganizationGrant numberCountry
Wellcome Trust France
National Natural Science Foundation of China (NSFC)31600606 China
National Basic Research Program of China (973 Program)2016YFA0501100 China
Citation
Journal: Cell / Year: 2021
Title: The epitope arrangement on flavivirus particles contributes to Mab C10's extraordinary neutralization breadth across Zika and dengue viruses.
Authors: Arvind Sharma / Xiaokang Zhang / Wanwisa Dejnirattisai / Xinghong Dai / Danyang Gong / Wiyada Wongwiwat / Stéphane Duquerroy / Alexander Rouvinski / Marie-Christine Vaney / Pablo Guardado- ...Authors: Arvind Sharma / Xiaokang Zhang / Wanwisa Dejnirattisai / Xinghong Dai / Danyang Gong / Wiyada Wongwiwat / Stéphane Duquerroy / Alexander Rouvinski / Marie-Christine Vaney / Pablo Guardado-Calvo / Ahmed Haouz / Patrick England / Ren Sun / Z Hong Zhou / Juthathip Mongkolsapaya / Gavin R Screaton / Felix A Rey /
Abstract: The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative ...The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.
#1: Journal: Nature / Year: 2016
Title: Structural basis of potent Zika-dengue virus antibody cross-neutralization.
Authors: Barba-Spaeth, G. / Dejnirattisai, W. / Rouvinski, A. / Vaney, M.C. / Medits, I. / Sharma, A. / Simon-Loriere, E. / Sakuntabhai, A. / Cao-Lormeau, V.M. / Haouz, A. / England, P. / Stiasny, K. ...Authors: Barba-Spaeth, G. / Dejnirattisai, W. / Rouvinski, A. / Vaney, M.C. / Medits, I. / Sharma, A. / Simon-Loriere, E. / Sakuntabhai, A. / Cao-Lormeau, V.M. / Haouz, A. / England, P. / Stiasny, K. / Mongkolsapaya, J. / Heinz, F.X. / Screaton, G.R. / Rey, F.A.
History
DepositionAug 19, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year

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Structure visualization

Movie
  • 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
  • EMDB-30465
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  • Superimposition on EM map
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Core protein
B: Core protein
C: Core protein
F: Core protein
D: Core protein
E: Core protein
I: Single Chain Variable Fragment
M: Single Chain Variable Fragment
H: Single Chain Variable Fragment
L: Single Chain Variable Fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)251,60114
Polymers250,71710
Non-polymers8854
Water0
1
A: Core protein
B: Core protein
C: Core protein
F: Core protein
D: Core protein
E: Core protein
I: Single Chain Variable Fragment
M: Single Chain Variable Fragment
H: Single Chain Variable Fragment
L: Single Chain Variable Fragment
hetero molecules
x 60


Theoretical massNumber of molelcules
Total (without water)15,096,081840
Polymers15,042,992600
Non-polymers53,090240
Water0
TypeNameSymmetry operationNumber
point symmetry operation60
Buried area30480 Å2
ΔGint-158 kcal/mol
Surface area92160 Å2
2


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
point symmetry operation1
3
A: Core protein
B: Core protein
C: Core protein
F: Core protein
D: Core protein
E: Core protein
I: Single Chain Variable Fragment
M: Single Chain Variable Fragment
H: Single Chain Variable Fragment
L: Single Chain Variable Fragment
hetero molecules
x 5


  • icosahedral pentamer
  • 1.26 MDa, 50 polymers
Theoretical massNumber of molelcules
Total (without water)1,258,00770
Polymers1,253,58350
Non-polymers4,42420
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
A: Core protein
B: Core protein
C: Core protein
F: Core protein
D: Core protein
E: Core protein
I: Single Chain Variable Fragment
M: Single Chain Variable Fragment
H: Single Chain Variable Fragment
L: Single Chain Variable Fragment
hetero molecules
x 6


  • icosahedral 23 hexamer
  • 1.51 MDa, 60 polymers
Theoretical massNumber of molelcules
Total (without water)1,509,60884
Polymers1,504,29960
Non-polymers5,30924
Water0
TypeNameSymmetry operationNumber
point symmetry operation6
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 Core protein / Capsid / Envelope protein E / Matrix protein / Peptide pr / Protein prM / Small envelope protein M


Mass: 54351.746 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus 2 / Cell line (production host): C6/36 / Production host: Aedes albopictus (Asian tiger mosquito) / References: UniProt: Q88636
#2: Protein Core protein / Capsid / Envelope protein E / Flavivirin protease NS2B regulatory subunit / Flavivirin protease NS3 ...Envelope protein E / Flavivirin protease NS2B regulatory subunit / Flavivirin protease NS3 catalytic subunit / Genome polyprotein / Matrix protein / Non-structural protein 1 / Non-structural protein 2A / Non-structural protein 2B / Non-structural protein 3 / Non-structural protein 4A / Non-structural protein 4B / Peptide 2k / Peptide pr / Protein prM / RNA-directed RNA polymerase NS5 / Serine protease NS3 / Serine protease subunit NS2B / Small envelope protein M


Mass: 8345.762 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus 2 / Gene: POLY / Cell line (production host): C6/36 / Production host: Aedes albopictus (Asian tiger mosquito)
References: UniProt: Q20II5, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase
#3: Antibody Single Chain Variable Fragment / Single-chain variable fragment


Mass: 15679.234 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: heavy chain variable region of the broadly neutralizing antibody EDE1 C10
Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly)
#4: Antibody Single Chain Variable Fragment / Single-chain variable fragment


Mass: 15632.767 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: light chain variable region of the broadly neutralizing antibody EDE1 C10
Source: (gene. exp.) Homo sapiens (human) / Production host: Drosophila melanogaster (fruit fly)
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN

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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: Dengue virus / Type: VIRUS / Entity ID: #2-#4 / Source: NATURAL
Source (natural)Organism: Dengue virus
Details of virusEmpty: NO / Enveloped: YES / Isolate: SEROTYPE / Type: VIRION
Natural hostOrganism: Homo sapiens
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
10RELIONinitial Euler assignment
11EMAN2initial Euler assignment
12cisTEMinitial Euler assignment
15cisTEM3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4977 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00348281
ELECTRON MICROSCOPYf_angle_d0.61765291
ELECTRON MICROSCOPYf_dihedral_angle_d4.3496504
ELECTRON MICROSCOPYf_chiral_restr0.0447487
ELECTRON MICROSCOPYf_plane_restr0.0048179

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