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- EMDB-21496: Human mAbs broadly protect against infection of arthritiogenic al... -

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Basic information

Entry
Database: EMDB / ID: EMD-21496
TitleHuman mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain
Map datanot sharpened
Sample
  • Complex: Chikungunya virus-Fab complex
    • Complex: Fab CHK-265
      • Protein or peptide: Fab CHK-265 heavy chain
      • Protein or peptide: Fab CHK-265 light chain
    • Virus: Chikungunya virus
      • Protein or peptide: E1 glycoprotein
      • Protein or peptide: E2 glycoprotein
      • Protein or peptide: E3
Keywordsvirus / monoclonal antibody / complex / VIRUS-IMMUNE SYSTEM complex
Function / homology
Function and homology information


T=4 icosahedral viral capsid / host cell cytoplasm / symbiont entry into host cell / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / proteolysis ...T=4 icosahedral viral capsid / host cell cytoplasm / symbiont entry into host cell / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / proteolysis / plasma membrane / cytoplasm
Similarity search - Function
Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein ...Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein / Alphavirus E1 glycoprotein / Alphavirus core protein (CP) domain profile. / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / Immunoglobulin E-set / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Structural polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Chikungunya virus
Methodsingle particle reconstruction / cryo EM / Resolution: 5.3 Å
AuthorsMiller AS / Kuhn RJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Cell Host Microbe / Year: 2020
Title: Human mAbs Broadly Protect against Arthritogenic Alphaviruses by Recognizing Conserved Elements of the Mxra8 Receptor-Binding Site.
Authors: Laura A Powell / Andrew Miller / Julie M Fox / Nurgun Kose / Thomas Klose / Arthur S Kim / Robin Bombardi / Rashika N Tennekoon / A Dharshan de Silva / Robert H Carnahan / Michael S Diamond ...Authors: Laura A Powell / Andrew Miller / Julie M Fox / Nurgun Kose / Thomas Klose / Arthur S Kim / Robin Bombardi / Rashika N Tennekoon / A Dharshan de Silva / Robert H Carnahan / Michael S Diamond / Michael G Rossmann / Richard J Kuhn / James E Crowe /
Abstract: Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease ...Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease burden, no approved therapies or licensed vaccines exist. Here, we describe human monoclonal antibodies (mAbs) that bind to and neutralize multiple distantly related alphaviruses. These mAbs compete for an antigenic site and prevent attachment to the recently discovered Mxra8 alphavirus receptor. Three cryoelectron microscopy structures of Fab in complex with Ross River (RRV), Mayaro, or chikungunya viruses reveal a conserved footprint of the broadly neutralizing mAb RRV-12 in a region of the E2 glycoprotein B domain. This mAb neutralizes virus in vitro by preventing virus entry and spread and is protective in vivo in mouse models. Thus, the RRV-12 mAb and its defined epitope have potential as a therapeutic agent or target of vaccine design against multiple emerging arthritogenic alphavirus infections.
History
DepositionFeb 29, 2020-
Header (metadata) releaseApr 1, 2020-
Map releaseAug 26, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4.9
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 4.9
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6w09
  • Surface level: 4.9
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6w09
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21496.png

Downloads & links

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Map

FileDownload / File: emd_21496.map.gz / Format: CCP4 / Size: 1.1 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationnot sharpened
Voxel sizeX=Y=Z: 1.62 Å
Density
Contour LevelBy AUTHOR: 4.9 / Movie #1: 4.9
Minimum - Maximum-18.688842999999999 - 18.112694000000001
Average (Standard dev.)0.08348658 (±1.477645)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-336-336-336
Dimensions672672672
Spacing672672672
CellA=B=C: 1088.64 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.621.621.62
M x/y/z672672672
origin x/y/z0.0000.0000.000
length x/y/z1088.6401088.6401088.640
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-336-336-336
NC/NR/NS672672672
D min/max/mean-18.68918.1130.083

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Supplemental data

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Half map: half map not sharpened

Fileemd_21496_half_map_1.map
Annotationhalf map not sharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map not sharpened

Fileemd_21496_half_map_2.map
Annotationhalf map not sharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Chikungunya virus-Fab complex

EntireName: Chikungunya virus-Fab complex
Components
  • Complex: Chikungunya virus-Fab complex
    • Complex: Fab CHK-265
      • Protein or peptide: Fab CHK-265 heavy chain
      • Protein or peptide: Fab CHK-265 light chain
    • Virus: Chikungunya virus
      • Protein or peptide: E1 glycoprotein
      • Protein or peptide: E2 glycoprotein
      • Protein or peptide: E3

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Supramolecule #1: Chikungunya virus-Fab complex

SupramoleculeName: Chikungunya virus-Fab complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #3: Fab CHK-265

SupramoleculeName: Fab CHK-265 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Chikungunya virus

SupramoleculeName: Chikungunya virus / type: virus / ID: 2 / Parent: 1 / Macromolecule list: #1-#2, #5 / NCBI-ID: 37124 / Sci species name: Chikungunya virus / Sci species strain: 181/25 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: No

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Macromolecule #1: E1 glycoprotein

MacromoleculeName: E1 glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Chikungunya virus / Strain: 181/25
Molecular weightTheoretical: 42.72123 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: YEHVTVIPNT VGVPYKTLVN RPGYSPMVLE MELLSVTLEP TLSLDYITCE YKTVIPSPYV KCCGTAECKD KSLPDYSCKV FTGVYPFMW GGAYCFCDTE NTQLSEAHVE KSESCKTEFA SAYRAHTASA SAKLRVLYQG NNVTVSAYAN GDHAVTVKDA K FIVGPMSS ...String:
YEHVTVIPNT VGVPYKTLVN RPGYSPMVLE MELLSVTLEP TLSLDYITCE YKTVIPSPYV KCCGTAECKD KSLPDYSCKV FTGVYPFMW GGAYCFCDTE NTQLSEAHVE KSESCKTEFA SAYRAHTASA SAKLRVLYQG NNVTVSAYAN GDHAVTVKDA K FIVGPMSS AWTPFDNKIV VYKGDVYNMD YPPFGAGRPG QFGDIQSRTP ESEDVYANTQ LVLQRPSAGT VHVPYSQAPS GF KYWLKER GASLQHTAPF GCQIATNPVR AMNCAVGNMP ISIDIPDAAF TRVVDAPSLT DMSCEVPACT HSSDFGGVAI IKY AASKKG KCAVHSMTNA VTIREAEIEV EGNSQLQISF STALASAEFR VQVCSTQVHC AAECHPPKDH IVNYPAS

UniProtKB: Structural polyprotein

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Macromolecule #2: E2 glycoprotein

MacromoleculeName: E2 glycoprotein / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Chikungunya virus / Strain: 181/25
Molecular weightTheoretical: 38.266254 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: NFNVYKAIRP YLAHCPDCGE GHSCHSPVAL ERIRNEATDG TLKIQVSLQI GIKTDDSHDW TKLRYMDNHM PADAERARLF VRTSAPCTI TGTMGHFILA RCPKGETLTV GFTDSGKISH SCTHPFHHDP PVIGREKFHS RPQHRKELPC STYAQSTAAT A EEIEVHMP ...String:
NFNVYKAIRP YLAHCPDCGE GHSCHSPVAL ERIRNEATDG TLKIQVSLQI GIKTDDSHDW TKLRYMDNHM PADAERARLF VRTSAPCTI TGTMGHFILA RCPKGETLTV GFTDSGKISH SCTHPFHHDP PVIGREKFHS RPQHRKELPC STYAQSTAAT A EEIEVHMP PDTPDRTLMS QQSGNVKITV NSQTVRYKCN CGDSNEGLTT TDKVINNCKV DQCHAAVTNH KKWQYNSPLV PR NAELGDR KGKVHIPFPL ANVTCRVPKA RNPTVTYGKN QVIMLLYPDH PTLLSYRNMG EEPNYQEEWV THKKEVIRTV PTE GLEVTW GNNEPYKYWP QL

UniProtKB: Structural polyprotein

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Macromolecule #3: Fab CHK-265 heavy chain

MacromoleculeName: Fab CHK-265 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.743719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QIQLVQSGRE VKNPGETVKI SCKASGYTFT EYPMLWVKQA PGKGFRWMGL IYTNTGEPTY AEEFKGRFVF SLEISASTAY LQINNLTNE DTATYFCVRD YFISLDYWGQ GTTLTVSSAK TTAPSVYPLA PVCGGTTGSS VTLGCLVKGY FPEPVTLTWN S GSLSSGVH ...String:
QIQLVQSGRE VKNPGETVKI SCKASGYTFT EYPMLWVKQA PGKGFRWMGL IYTNTGEPTY AEEFKGRFVF SLEISASTAY LQINNLTNE DTATYFCVRD YFISLDYWGQ GTTLTVSSAK TTAPSVYPLA PVCGGTTGSS VTLGCLVKGY FPEPVTLTWN S GSLSSGVH TFPALLQSGL YTLSSSVTVT SNTWPSQTIT CNVAHPASST KVDKKIESRR

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Macromolecule #4: Fab CHK-265 light chain

MacromoleculeName: Fab CHK-265 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.888404 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QAVVTQESAL TTSPGETVTL TCRSNIGAVT SSNCANWVQE KPDHFFTGLI GDTNNRRSGV PARFSGSLIG DKAALTITGA QTEDEAIYF CALWYNNLWV FGGGTKLTVL GQPKSSPSVT LFPPSSEELE TNKATLVCTI TDFYPGVVTV DWKVDGTPVT Q GMETTQPS ...String:
QAVVTQESAL TTSPGETVTL TCRSNIGAVT SSNCANWVQE KPDHFFTGLI GDTNNRRSGV PARFSGSLIG DKAALTITGA QTEDEAIYF CALWYNNLWV FGGGTKLTVL GQPKSSPSVT LFPPSSEELE TNKATLVCTI TDFYPGVVTV DWKVDGTPVT Q GMETTQPS KQSNNKYMAS SYLTLTARAW ERHSSYSCQV THEGHTVEKS LSR

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Macromolecule #5: E3

MacromoleculeName: E3 / type: protein_or_peptide / ID: 5 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Chikungunya virus / Strain: 181/25
Molecular weightTheoretical: 6.904067 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString:
PVMCLLANTT FPCSQPPCTP CCYEKEPEKT LRMLEDNVMS PGYYQLLQAS LTCSPRRQRR

UniProtKB: Structural polyprotein

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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

Concentration3 mg/mL
BufferpH: 7.5
GridModel: C-flat / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Instrument: GATAN CRYOPLUNGE 3

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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 magnification: 18000
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 BASE (4k x 4k) / Average electron dose: 30.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING / Software - Name: jspr
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 5.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr / Number images used: 10395

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-6w09:
Human mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain

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