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- EMDB-21509: Human mAbs broadly protect against infection of arthritiogenic al... -

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Basic information

Entry
Database: EMDB / ID: EMD-21509
TitleHuman mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain
Map dataunsharpened map
Sample
  • Complex: Mayaro virus-Fab CHK-265 complex
    • Complex: Fab CHK-265
      • Protein or peptide: Fab CHK-265 heavy chain
      • Protein or peptide: Fab CHK-265 light chain
    • Virus: Mayaro virus
      • Protein or peptide: E1 glycoprotein
      • Protein or peptide: E2 glycoprotein
Keywordsvirus / monoclonal antibody / complex / VIRUS-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 / symbiont entry into host cell / 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 / symbiont entry into host cell / 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 / proteolysis / RNA binding / membrane
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) / Mayaro virus (strain Brazil) / Mayaro 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
DepositionMar 4, 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: 4.8
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 4.8
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6w1c
  • Surface level: 4.8
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6w1c
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21509.png

Downloads & links

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Map

FileDownload / File: emd_21509.map.gz / Format: CCP4 / Size: 1.1 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationunsharpened map
Voxel sizeX=Y=Z: 1.62 Å
Density
Contour LevelBy AUTHOR: 4.8 / Movie #1: 4.8
Minimum - Maximum-14.419654 - 31.052876000000001
Average (Standard dev.)0.056842163 (±1.4025003)
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
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS-336-336-336
NC/NR/NS672672672
D min/max/mean-14.42031.0530.057

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Supplemental data

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Half map: half map 1, unsharpened

Fileemd_21509_half_map_1.map
Annotationhalf map 1, unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 3, unsharpened

Fileemd_21509_half_map_2.map
Annotationhalf map 3, unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Mayaro virus-Fab CHK-265 complex

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

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Supramolecule #1: Mayaro virus-Fab CHK-265 complex

SupramoleculeName: Mayaro virus-Fab CHK-265 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: Mayaro virus

SupramoleculeName: Mayaro virus / type: virus / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 / NCBI-ID: 59301 / Sci species name: Mayaro virus / 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: Mayaro virus (strain Brazil) / Strain: Brazil
Molecular weightTheoretical: 41.612867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: YEHTAIIPNQ VGFPYKAHVA REGYSPLTLQ MQVIETSLEP TLNLEYITCD YKTKVPSPYV KCCGTAECRT QDKPEYKCAV FTGVYPFMW GGAYCFCDSE NTQMSEAYVE RADVCKHDHA AAYRAHTASL RAKIKVTYGT VNQTVEAYVN GDHAVTIAGT K FIFGPVST ...String:
YEHTAIIPNQ VGFPYKAHVA REGYSPLTLQ MQVIETSLEP TLNLEYITCD YKTKVPSPYV KCCGTAECRT QDKPEYKCAV FTGVYPFMW GGAYCFCDSE NTQMSEAYVE RADVCKHDHA AAYRAHTASL RAKIKVTYGT VNQTVEAYVN GDHAVTIAGT K FIFGPVST PWTPFDTKIL VYKGELYNQD FPRYGAGQPG RFGDIQSRTL DSRDLYANTG LKLARPAAGN IHVPYTQTPS GF KTWQKDR DSPLNAKAPF GCIIQTNPVR AMNCAVGNIP VSMDIADSAF TRLTDAPVIS ELTCTVSTCT HSSDFGGIAV LSY KVEKSG RCDIHSHSNV AVLQEVSIET EGRSVIHFST ASASPSFVVS VCSSRATCTA KCEP

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: Mayaro virus (strain Brazil) / Strain: Brazil
Molecular weightTheoretical: 38.041957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: STANHFNAYK LTRPYVAYCA DCGMGHSCHS PAMIENIQAD ATDGTLKIQF ASQIGLTKTD THDHTKIRYA EGHDIAEAAR STLKVHSSS ECTVTGTMGH FILAKCPPGE RISVSFVDSK NEHRTCRIAY HHEQRLIGRE RFTVRPHHGI ELPCTTYQLT T AETSEEID ...String:
STANHFNAYK LTRPYVAYCA DCGMGHSCHS PAMIENIQAD ATDGTLKIQF ASQIGLTKTD THDHTKIRYA EGHDIAEAAR STLKVHSSS ECTVTGTMGH FILAKCPPGE RISVSFVDSK NEHRTCRIAY HHEQRLIGRE RFTVRPHHGI ELPCTTYQLT T AETSEEID MHMPPDIPDR TILSQQSGNV KITVNGRTVR YSSSCGSQAV GTTTTDKTIN SCTVDKCQAY VTSHTKWQFN SP FVPRRMQ AERKGKVHIP FPLINTTCRV PLAPEALVRS GKREATLSLH PIHPTLLSYR TFGAERVFDE QWITAQTEVT IPV PVEGVE YQWGNHKPQR FVVA

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 / 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: 18410

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-6w1c:
Human mAbs broadly protect against infection of arthritiogenic alphaviruses by recognizing conserved elements of the MXR8 receptor binding domain

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