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- EMDB-21473: Human mAbs broadly protect against infection of arthritiogenic al... -

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Basic information

Entry
Database: EMDB / ID: EMD-21473
TitleHuman mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain
Map dataunsharpened map
Sample
  • Virus: Ross river virus (strain T48)
    • Protein or peptide: E1 glycoprotein
    • Protein or peptide: E2 glycoprotein
  • Protein or peptide: Fab CHK-265 heavy chain
  • Protein or peptide: Fab CHK-265 light chain
Keywordsvirus / monoclonal antibody / complex / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / membrane => GO:0016020 / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / host cell nucleus / virion attachment to host cell / host cell plasma membrane ...togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / membrane => GO:0016020 / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / RNA binding
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 speciesRoss river virus (strain T48) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.33 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)11000864 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 27, 2020-
Header (metadata) releaseMar 25, 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: 3
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vyv
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6vyv
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21473.png

Downloads & links

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Map

FileDownload / File: emd_21473.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationunsharpened map
Voxel sizeX=Y=Z: 1.62 Å
Density
Contour LevelBy AUTHOR: 3.0 / Movie #1: 3
Minimum - Maximum-8.720488 - 10.955368
Average (Standard dev.)0.054165956 (±1.3145721)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-250-250-250
Dimensions500500500
Spacing500500500
CellA=B=C: 810.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.621.621.62
M x/y/z500500500
origin x/y/z0.0000.0000.000
length x/y/z810.000810.000810.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS-250-250-250
NC/NR/NS500500500
D min/max/mean-8.72010.9550.054

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Supplemental data

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Half map: unsharpened odd half map

Fileemd_21473_half_map_1.map
Annotationunsharpened odd half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: unsharpened even half map

Fileemd_21473_half_map_2.map
Annotationunsharpened even half 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 : Ross river virus (strain T48)

EntireName: Ross river virus (strain T48)
Components
  • Virus: Ross river virus (strain T48)
    • Protein or peptide: E1 glycoprotein
    • Protein or peptide: E2 glycoprotein
  • Protein or peptide: Fab CHK-265 heavy chain
  • Protein or peptide: Fab CHK-265 light chain

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Supramolecule #1: Ross river virus (strain T48)

SupramoleculeName: Ross river virus (strain T48) / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 / NCBI-ID: 11032 / Sci species name: Ross river virus (strain T48) / 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 / EC number: togavirin
Source (natural)Organism: Ross river virus (strain T48) / Strain: T48
Molecular weightTheoretical: 42.719906 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: YEHTATIPNV VGFPYKAHIE RNGFSPMTLQ LEVVETSWEP TLNLEYITCE YKTVVPSPFI KCCGTSECSS KEQPDYQCKV YTGVYPFMW GGAYCFCDSE NTQLSEAYVD RSDVCKHDHA SAYKAHTASL KATIRISYGT INQTTEAFVN GEHAVNVGGS K FIFGPIST ...String:
YEHTATIPNV VGFPYKAHIE RNGFSPMTLQ LEVVETSWEP TLNLEYITCE YKTVVPSPFI KCCGTSECSS KEQPDYQCKV YTGVYPFMW GGAYCFCDSE NTQLSEAYVD RSDVCKHDHA SAYKAHTASL KATIRISYGT INQTTEAFVN GEHAVNVGGS K FIFGPIST AWSPFDNKIV VYKDDVYNQD FPPYGSGQPG RFGDIQSRTV ESKDLYANTA LKLSRPSPGV VHVPYTPTPS GF KYWLKEK GSSLNTKAPF GCKIKTNPVR AMDCAVGSIP VSMDIPDSAF TRVVDAPAVT DLSCQVVVCT HSSDFGGVAT LSY KTDKPG KCAVHSHSNV ATLQEATVDV KEDGKVTVHF STASASPAFK VSVCDAKTTC TAACEPPKDH IVPYGAS

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 / EC number: togavirin
Source (natural)Organism: Ross river virus (strain T48) / Strain: T48
Molecular weightTheoretical: 38.240188 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: SVTEHFNVYK ATRPYLAYCA DCGDGYFCYS PVAIEKIRDE APDGMLKIQV SAQIGLDKAG THAHTKIRYM AGHDVQESKR DSLRVYTSA ACSIHGTMGH FIVAHCPPGD YLKVSFEDAD SHVKACKVQY KHDPLPVGRE KFVVRPHFGV ELPCTSYQLT T APTDEEID ...String:
SVTEHFNVYK ATRPYLAYCA DCGDGYFCYS PVAIEKIRDE APDGMLKIQV SAQIGLDKAG THAHTKIRYM AGHDVQESKR DSLRVYTSA ACSIHGTMGH FIVAHCPPGD YLKVSFEDAD SHVKACKVQY KHDPLPVGRE KFVVRPHFGV ELPCTSYQLT T APTDEEID MHTPPDIPDR TLLSQTAGNV KITAGGRTIR YNCTCGRDNV GTTSTDKTIN TCKIDQCHAA VTSHDKWQFT SP FVPRADQ TARRGKVHVP FPLTNVTCRV PLARAPDVTY GKKEVTLRLH PDHPTLFSYR SLGAEPHPYE EWVDKFSERI IPV TEEGIE YQWGNNPPVR LWAQL

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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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 / Material: COPPER / 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: 6.33 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr / Number images used: 9559

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

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

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