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- PDB-8fe4: Structure of dengue virus (DENV2) in complex with prM13, an anti-... -

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Basic information

Entry
Database: PDB / ID: 8fe4
TitleStructure of dengue virus (DENV2) in complex with prM13, an anti-PrM monoclonal antibody
Components
  • Envelope protein E
  • prM protein
  • prM13 Fab Heavy Chain
  • prM13 Fab Light Chain
KeywordsVIRUS/IMMUNE SYSTEM / DENV / flavivirus / prM antibody / prM13 / VIRUS-IMMUNE SYSTEM complex
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 speciesDengue virus type 2
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 9.8 Å
AuthorsDowd, A.D. / Sirohi, D. / Speer, S. / Mukherjee, S. / Govero, J. / Aleshnick, M. / Larman, B. / Sukupolvi-Petty, S. / Sevvana, M. / Miller, A.S. ...Dowd, A.D. / Sirohi, D. / Speer, S. / Mukherjee, S. / Govero, J. / Aleshnick, M. / Larman, B. / Sukupolvi-Petty, S. / Sevvana, M. / Miller, A.S. / Klose, T. / Zheng, A. / Kielian, M. / Kuhn, R.J. / Diamond, M.S. / Pierson, T.C.
Funding support United States, 2items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: pdbx_database_related

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Envelope protein E
B: prM protein
H: prM13 Fab Heavy Chain
L: prM13 Fab Light Chain
C: Envelope protein E
D: prM protein
M: prM13 Fab Heavy Chain
N: prM13 Fab Light Chain
E: Envelope protein E
F: prM protein
O: prM13 Fab Heavy Chain
P: prM13 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)300,53112
Polymers300,53112
Non-polymers00
Water0
1
A: Envelope protein E
B: prM protein
H: prM13 Fab Heavy Chain
L: prM13 Fab Light Chain
C: Envelope protein E
D: prM protein
M: prM13 Fab Heavy Chain
N: prM13 Fab Light Chain
E: Envelope protein E
F: prM protein
O: prM13 Fab Heavy Chain
P: prM13 Fab Light Chain
x 60


Theoretical massNumber of molelcules
Total (without water)18,031,890720
Polymers18,031,890720
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 E
B: prM protein
H: prM13 Fab Heavy Chain
L: prM13 Fab Light Chain
C: Envelope protein E
D: prM protein
M: prM13 Fab Heavy Chain
N: prM13 Fab Light Chain
E: Envelope protein E
F: prM protein
O: prM13 Fab Heavy Chain
P: prM13 Fab Light Chain
x 5


  • icosahedral pentamer
  • 1.5 MDa, 60 polymers
Theoretical massNumber of molelcules
Total (without water)1,502,65760
Polymers1,502,65760
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: Envelope protein E
B: prM protein
H: prM13 Fab Heavy Chain
L: prM13 Fab Light Chain
C: Envelope protein E
D: prM protein
M: prM13 Fab Heavy Chain
N: prM13 Fab Light Chain
E: Envelope protein E
F: prM protein
O: prM13 Fab Heavy Chain
P: prM13 Fab Light Chain
x 6


  • icosahedral 23 hexamer
  • 1.8 MDa, 72 polymers
Theoretical massNumber of molelcules
Total (without water)1,803,18972
Polymers1,803,18972
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 E /


Mass: 43892.469 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus type 2 / Cell line (production host): C6/36 / Production host: Aedes albopictus (Asian tiger mosquito) / References: UniProt: A0A481XTV0
#2: Protein prM protein


Mass: 9261.531 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus type 2 / Cell line (production host): C6/36 / Production host: Aedes albopictus (Asian tiger mosquito) / References: UniProt: A0A481XTV0
#3: Antibody prM13 Fab Heavy Chain


Mass: 23777.656 Da / Num. of mol.: 3 / Mutation: X1A,X2A
Source method: isolated from a genetically manipulated source
Details: The homology model of the prM13 variable heavy chain domain (1-118) 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 prM13 variable heavy chain domain (1-118) 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 prM13.
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): HEK293T/17 / Production host: Homo sapiens (human)
#4: Antibody prM13 Fab Light Chain


Mass: 23245.510 Da / Num. of mol.: 3 / Mutation: X1A,X4A,X106A,X103A
Source method: isolated from a genetically manipulated source
Details: The homology model of the prM13 variable light chain domain (1-106) 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 prM13 variable light chain domain (1-106) 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 prM13.
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): HEK293T/17 / Production host: 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

ComponentName: Mus musculusHouse mouse / Type: VIRUS / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Dengue virus 211060
21Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Aedes albopictus (Asian tiger mosquito)7160
Details of virusEmpty: NO / Enveloped: YES / Isolate: SEROTYPE / Type: VIRION
Virus shellDiameter: 500 nm / Triangulation number (T number): 3
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: PELCO Ultrathin Carbon with Lacey Carbon
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 / Nominal magnification: 81000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 30 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategory
2Leginonimage acquisition
7UCSF Chimeramodel fitting
13jspr3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 9.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 5458 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-ID
13C6E

3c6e

1
25KVG

5kvg

1
RefinementHighest resolution: 9.8 Å

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