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- PDB-8hxc: Cryo-EM structure of MPXV M2 heptamer in complex with human B7.2 -

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Basic information

Entry
Database: PDB / ID: 8hxc
TitleCryo-EM structure of MPXV M2 heptamer in complex with human B7.2
Components
  • NFkB inhibitor
  • T-lymphocyte activation antigen CD86
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / M2 / complex / immune evasion / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 / B cell activation / positive regulation of interleukin-4 production ...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 / B cell activation / positive regulation of interleukin-4 production / 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 / T cell activation / positive regulation of interleukin-2 production / 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 speciesMonkeypox virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsWang, Y. / Yang, S. / Zhao, H. / Deng, Z.
Funding support1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NFkB inhibitor
B: NFkB inhibitor
C: NFkB inhibitor
D: NFkB inhibitor
E: NFkB inhibitor
F: NFkB inhibitor
G: NFkB inhibitor
H: T-lymphocyte activation antigen CD86
I: T-lymphocyte activation antigen CD86
J: T-lymphocyte activation antigen CD86
K: T-lymphocyte activation antigen CD86
L: T-lymphocyte activation antigen CD86
M: T-lymphocyte activation antigen CD86
N: T-lymphocyte activation antigen CD86


Theoretical massNumber of molelcules
Total (without water)333,94214
Polymers333,94214
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
NFkB inhibitor


Mass: 23285.348 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Monkeypox virus / Gene: O2L / Production host: Homo sapiens (human) / References: UniProt: Q3I8Y9
#2: Protein
T-lymphocyte activation antigen CD86 / Activation B7-2 antigen / B70 / BU63 / CTLA-4 counter-receptor B7.2 / FUN-1


Mass: 24420.646 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD86, CD28LG2 / Production host: Homo sapiens (human) / References: UniProt: P42081

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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: M2-hB7.2 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45302 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00717738
ELECTRON MICROSCOPYf_angle_d1.19824010
ELECTRON MICROSCOPYf_dihedral_angle_d5.6322338
ELECTRON MICROSCOPYf_chiral_restr0.0682667
ELECTRON MICROSCOPYf_plane_restr0.0063066

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