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- EMDB-29020: Structure of dengue virus (DENV2) in complex with prM12, an anti-... -

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Basic information

Entry
Database: EMDB / ID: EMD-29020
TitleStructure of dengue virus (DENV2) in complex with prM12, an anti-PrM monoclonal antibody
Map data
SampleMus musculus != Dengue virus 2

Mus musculus

  • Virus: Dengue virus 2
    • Protein or peptide: prM12 Fab Heavy Chain
    • Protein or peptide: prM12 Fab Light Chain
    • Protein or peptide: Envelope protein E
    • Protein or peptide: prM protein
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / viral capsid / double-stranded RNA binding / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / viral capsid / double-stranded RNA binding / 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 / protein dimerization activity / 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 / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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 ...RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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 speciesMus musculus (house mouse) / Dengue virus type 2 / Dengue virus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 10.2 Å
AuthorsDowd AD / Sirohi D / Speer S / Mukherjee S / Govero J / Aleshnick M / Larman B / Sukupolvi-Petty S / Sevvana M / Miller AS ...Dowd AD / Sirohi D / Speer S / Mukherjee S / Govero J / Aleshnick M / Larman B / Sukupolvi-Petty S / Sevvana M / Miller AS / Klose T / Zheng A / Kielian M / Kuhn RJ / Diamond MS / Pierson TC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI073755 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI011219 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.
Authors: Kimberly A Dowd / Devika Sirohi / Scott D Speer / Laura A VanBlargan / Rita E Chen / Swati Mukherjee / Bradley M Whitener / Jennifer Govero / Maya Aleshnick / Bridget Larman / Soila ...Authors: Kimberly A Dowd / Devika Sirohi / Scott D Speer / Laura A VanBlargan / Rita E Chen / Swati Mukherjee / Bradley M Whitener / Jennifer Govero / Maya Aleshnick / Bridget Larman / Soila Sukupolvi-Petty / Madhumati Sevvana / Andrew S Miller / Thomas Klose / Aihua Zheng / Scott Koenig / Margaret Kielian / Richard J Kuhn / Michael S Diamond / Theodore C Pierson /
Abstract: Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis ...Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM virions can also contribute to pathogenesis during primary DENV infections.
History
DepositionDec 5, 2022-
Header (metadata) releaseFeb 1, 2023-
Map releaseFeb 1, 2023-
UpdateApr 5, 2023-
Current statusApr 5, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29020.png

Downloads & links

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Map

FileDownload / File: emd_29020.map.gz / Format: CCP4 / Size: 1000 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.73 Å
Density
Contour LevelBy AUTHOR: 1.8
Minimum - Maximum-7.198555 - 10.0133095
Average (Standard dev.)0.026163522 (±0.63333756)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-320-320-320
Dimensions640640640
Spacing640640640
CellA=B=C: 1107.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_29020_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29020_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 : Mus musculus

EntireName: Mus musculus (house mouse)
Components
  • Virus: Dengue virus 2
    • Protein or peptide: prM12 Fab Heavy Chain
    • Protein or peptide: prM12 Fab Light Chain
    • Protein or peptide: Envelope protein E
    • Protein or peptide: prM protein

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Supramolecule #1: Dengue virus 2

SupramoleculeName: Dengue virus 2 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: all / NCBI-ID: 11060 / Sci species name: Dengue virus 2 / Virus type: VIRION / Virus isolate: SEROTYPE / Virus enveloped: Yes / Virus empty: No
Virus shellShell ID: 1 / Diameter: 500.0 Å / T number (triangulation number): 3

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Macromolecule #1: prM12 Fab Heavy Chain

MacromoleculeName: prM12 Fab Heavy Chain / type: protein_or_peptide / ID: 1
Details: The homology model of the prM12 variable heavy chain domain (1-124) was pieced together with the crystal structure of the constant heavy chain domain, derived from ZV-67, which belongs to ...Details: The homology model of the prM12 variable heavy chain domain (1-124) was pieced together with the crystal structure of the constant heavy chain domain, derived from ZV-67, which belongs to murine IgG2c isotype similar to prM12.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.6165 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLQESGPE LVKPGTSVKM SCKASGYTFT DYNIHWVKQS HGKSLEWIGY INPNNGGNKY TQKFEGRATL TVGKSSSTAY MELRSLTSE DSAVYYCARS PMYFYYDGSY YFDYWGQGTS LSVSSAKTTA PSVYPLAPVC GGTTGSSVTL GCLVKGYFPE P VTLTWNSG ...String:
EVQLQESGPE LVKPGTSVKM SCKASGYTFT DYNIHWVKQS HGKSLEWIGY INPNNGGNKY TQKFEGRATL TVGKSSSTAY MELRSLTSE DSAVYYCARS PMYFYYDGSY YFDYWGQGTS LSVSSAKTTA PSVYPLAPVC GGTTGSSVTL GCLVKGYFPE P VTLTWNSG SLSSGVHTFP ALLQSGLYTL SSSVTVTSNT WPSQTITCNV AHPASSTKVD KKIEPRVPI

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Macromolecule #2: prM12 Fab Light Chain

MacromoleculeName: prM12 Fab Light Chain / type: protein_or_peptide / ID: 2
Details: The homology model of the prM12 variable light chain domain (1-108) was pieced together with the crystal structure of the constant light chain domain, derived from ZV-67, which belongs to ...Details: The homology model of the prM12 variable light chain domain (1-108) was pieced together with the crystal structure of the constant light chain domain, derived from ZV-67, which belongs to murine IgG2c isotype similar to prM12.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.530898 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVLTQSPAS LAVSLGQRAT ISYRASKSVS TSGYSYMHWN QQKPGQPPRL LIYLVSNLES GVPARFSGSG SGTDFTLNIH PVEEEDAAT YYCQHIRELT FGAAPSAAAR ADAAPTVSIF PPSSEQLTSG GASVVCFLNN FYPKDINVKW KIDGSERQNG V LNSWTDQD ...String:
DIVLTQSPAS LAVSLGQRAT ISYRASKSVS TSGYSYMHWN QQKPGQPPRL LIYLVSNLES GVPARFSGSG SGTDFTLNIH PVEEEDAAT YYCQHIRELT FGAAPSAAAR ADAAPTVSIF PPSSEQLTSG GASVVCFLNN FYPKDINVKW KIDGSERQNG V LNSWTDQD SKDSTYSMSS TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC

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Macromolecule #3: Envelope protein E

MacromoleculeName: Envelope protein E / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Dengue virus type 2
Molecular weightTheoretical: 43.892469 KDa
Recombinant expressionOrganism: Aedes albopictus (Asian tiger mosquito)
SequenceString: MRCIGMSNRD FVEGVSGGSW VDIVLEHGSC VTTMAKNKPT LDFELIKTEA KQPATLRKYC IEAKLTNTTT ESRCPTQGEP SLNEEQDKR FVCKHSMVDR GWGNGCGLFG KGGIVTCAMF RCKKNMEGKV VQPENLEYTI VITPHSGEEH AVGNDTGKHG K EIKITPQS ...String:
MRCIGMSNRD FVEGVSGGSW VDIVLEHGSC VTTMAKNKPT LDFELIKTEA KQPATLRKYC IEAKLTNTTT ESRCPTQGEP SLNEEQDKR FVCKHSMVDR GWGNGCGLFG KGGIVTCAMF RCKKNMEGKV VQPENLEYTI VITPHSGEEH AVGNDTGKHG K EIKITPQS SITEAELTGY GTVTMECSPR TGLDFNEMVL LQMENKAWLV HRQWFLDLPL PWLPGADTQG SNWIQKETLV TF KNPHAKK QDVVVLGSQE GAMHTALTGA TEIQMSSGNL LFTGHLKCRL RMDKLQLKGM SYSMCTGKFK VVKEIAETQH GTI VIRVQY EGDGSPCKIP FEIMDLEKRH VLGRLITVNP IVTEKDSPVN IEAEPPFGDS YIIIGVEPGQ LKLNWFKK

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Macromolecule #4: prM protein

MacromoleculeName: prM protein / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Dengue virus type 2
Molecular weightTheoretical: 9.261531 KDa
Recombinant expressionOrganism: Aedes albopictus (Asian tiger mosquito)
SequenceString:
FHLTTRNGEP HMIVSRQEKG KSLLFKTEDG VNMCTLMAMD LGELCEDTIT YKCPLLRQNE PEDIDCWCNS TSTWVTYGTC T

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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

Concentration5 mg/mL
BufferpH: 8
GridModel: PELCO Ultrathin Carbon with Lacey Carbon / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: LACEY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 30.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: jspr
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 10.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr / Number images used: 5881

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Atomic model buiding 1

Initial model(PDB ID:

3c6e

,

5kvg

)
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8fe3:
Structure of dengue virus (DENV2) in complex with prM12, an anti-PrM monoclonal antibody

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