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- EMDB-35075: Cryo-EM structure of MPXV M2 hexamer in complex with human B7.2 -

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Basic information

Entry
Database: EMDB / ID: EMD-35075
TitleCryo-EM structure of MPXV M2 hexamer in complex with human B7.2
Map data
Sample
  • Complex: M2-hB7.2
    • Protein or peptide: NFkB inhibitor
    • Protein or peptide: T-lymphocyte activation antigen CD86
KeywordsM2 / complex / immune evasion / VIRAL PROTEIN
Function / homology
Function and homology information


positive regulation of lymphotoxin A production / CD40 signaling pathway / positive regulation of T-helper 2 cell differentiation / activation of protein kinase C activity / CD28 co-stimulation / CD28 dependent Vav1 pathway / positive regulation of immunoglobulin production / CTLA4 inhibitory signaling / positive regulation of interleukin-4 production / B cell activation ...positive regulation of lymphotoxin A production / CD40 signaling pathway / positive regulation of T-helper 2 cell differentiation / activation of protein kinase C activity / CD28 co-stimulation / CD28 dependent Vav1 pathway / positive regulation of immunoglobulin production / CTLA4 inhibitory signaling / positive regulation of interleukin-4 production / B cell activation / Interleukin-10 signaling / CD28 dependent PI3K/Akt signaling / : / centriolar satellite / coreceptor activity / negative regulation of T cell proliferation / positive regulation of T cell proliferation / T cell costimulation / positive regulation of interleukin-2 production / T cell activation / positive regulation of non-canonical NF-kappaB signal transduction / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / virus receptor activity / signaling receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cellular response to lipopolysaccharide / adaptive immune response / receptor ligand activity / cell surface receptor signaling pathway / immune response / external side of plasma membrane / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / cell surface / extracellular exosome / plasma membrane
Similarity search - Function
Poxvirus M2 / Poxvirus M2 protein / CD86, IgV domain / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain ...Poxvirus M2 / Poxvirus M2 protein / CD86, IgV domain / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
T-lymphocyte activation antigen CD86 / Early protein OPG038
Similarity search - Component
Biological speciesHomo sapiens (human) / Monkeypox virus
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsWang Y / Yang S / Zhao H / Deng Z
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: Structural and functional insights into the modulation of T cell costimulation by monkeypox virus protein M2.
Authors: Shangyu Yang / Yong Wang / Feiyang Yu / Rao Cheng / Yiwei Zhang / Dan Zhou / Xuanxiu Ren / Zengqin Deng / Haiyan Zhao /
Abstract: The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the ...The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the poxvirus immune evasion family and plays roles in host immunomodulation via the regulation of innate immune response mediated by the NF-κB pathway and adaptive immune response mediated by B7 ligands. However, the interaction of monkeypox virus (MPXV) M2 with B7 ligands and structural insight into poxviral M2 function have remained elusive. Here we reveal that MPXV M2, co-existing as a hexamer and a heptamer, recognizes human B7.1 and B7.2 (hB7.1/2) with high avidities. The binding of oligomeric MPXV M2 interrupts the interactions of hB7.1/2 with CD28 and CTLA4 and subverts T cell activation mediated by B7.1/2 costimulatory signals. Cryo-EM structures of M2 in complex with hB7.1/2 show that M2 binds to the shallow concave face of hB7.1/2 and displays sterically competition with CD28 and CTLA4 for the binding to hB7.1/2. Our findings provide structural mechanisms of poxviral M2 function and immune evasion deployed by poxviruses.
History
DepositionJan 4, 2023-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35075.png

Downloads & links

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Map

FileDownload / File: emd_35075.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.95 Å
Density
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-2.6054614 - 3.1306412
Average (Standard dev.)0.0011085891 (±0.061479665)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 304.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35075_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35075_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 : M2-hB7.2

EntireName: M2-hB7.2
Components
  • Complex: M2-hB7.2
    • Protein or peptide: NFkB inhibitor
    • Protein or peptide: T-lymphocyte activation antigen CD86

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Supramolecule #1: M2-hB7.2

SupramoleculeName: M2-hB7.2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NFkB inhibitor

MacromoleculeName: NFkB inhibitor / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Monkeypox virus
Molecular weightTheoretical: 23.285348 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VEYKNTICPP RQDYRYWYFV AELTIGVNYD INSTIIGECH MSESYIDRNA NIVLTGYGLK INMTIMDTDQ RFVAAAEGVG KDNKLSVLL FTTQRLDKVH HNISVTITCM EMNCGTTKYN SDLPESIHKS SSCDITINGS CVTCVNLETD PTKINPHYLH P KNKYLYHN ...String:
VEYKNTICPP RQDYRYWYFV AELTIGVNYD INSTIIGECH MSESYIDRNA NIVLTGYGLK INMTIMDTDQ RFVAAAEGVG KDNKLSVLL FTTQRLDKVH HNISVTITCM EMNCGTTKYN SDLPESIHKS SSCDITINGS CVTCVNLETD PTKINPHYLH P KNKYLYHN SEYSMRGSYG VTFIDELNQC LLDIKELSYD ICYRE

UniProtKB: Early protein OPG038

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Macromolecule #2: T-lymphocyte activation antigen CD86

MacromoleculeName: T-lymphocyte activation antigen CD86 / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.420646 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LKIQAYFNET ADLPCQFANS QNQSLSELVV FWQDQENLVL NEVYLGKEKF DSVHSKYMGR TSFDSDSWTL RLHNLQIKDK GLYQCIIHH KKPTGMIRIH QMNSELSVLA NFSQPEIVPI SNITENVYIN LTCSSIHGYP EPKKMSVLLR TKNSTIEYDG V MQKSQDNV ...String:
LKIQAYFNET ADLPCQFANS QNQSLSELVV FWQDQENLVL NEVYLGKEKF DSVHSKYMGR TSFDSDSWTL RLHNLQIKDK GLYQCIIHH KKPTGMIRIH QMNSELSVLA NFSQPEIVPI SNITENVYIN LTCSSIHGYP EPKKMSVLLR TKNSTIEYDG V MQKSQDNV TELYDVSISL SVSFPDVTSN MTIFCILETD KTRLLSSPFS IELED

UniProtKB: T-lymphocyte activation antigen CD86

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 198500
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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