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

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Basic information

Entry
Database: PDB / ID: 8hxb
TitleCryo-EM structure of MPXV M2 hexamer in complex with human B7.2
Components
  • NFkB inhibitor
  • T-lymphocyte activation antigen CD86
KeywordsVIRAL PROTEIN / M2 / complex / immune evasion
Function / homology
Function and homology information


positive regulation of lymphotoxin A production / positive regulation of T-helper 2 cell differentiation / Co-stimulation by CD28 / CD28 dependent Vav1 pathway / positive regulation of immunoglobulin production / host cell endoplasmic reticulum / Co-inhibition by CTLA4 / positive regulation of interleukin-4 production / Interleukin-10 signaling / B cell activation ...positive regulation of lymphotoxin A production / positive regulation of T-helper 2 cell differentiation / Co-stimulation by CD28 / CD28 dependent Vav1 pathway / positive regulation of immunoglobulin production / host cell endoplasmic reticulum / Co-inhibition by CTLA4 / positive regulation of interleukin-4 production / Interleukin-10 signaling / B cell activation / CD28 dependent PI3K/Akt signaling / coreceptor activity / negative regulation of T cell proliferation / T cell costimulation / positive regulation of T cell proliferation / positive regulation of interleukin-2 production / T cell activation / positive regulation of non-canonical NF-kappaB signal transduction / centriolar satellite / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / signaling receptor activity / cellular response to lipopolysaccharide / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / symbiont-mediated suppression of host NF-kappaB cascade / adaptive immune response / cell surface receptor signaling pathway / immune response / receptor ligand activity / external side of plasma membrane / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / cell surface / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
CD86, IgV domain / Poxvirus M2 / Poxvirus M2 protein / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. ...CD86, IgV domain / Poxvirus M2 / Poxvirus M2 protein / : / 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: 2.7 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
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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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: T-lymphocyte activation antigen CD86
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


Theoretical massNumber of molelcules
Total (without water)286,23612
Polymers286,23612
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.: 6
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.: 6
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
Has protein modificationY

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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: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 198500 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00715204
ELECTRON MICROSCOPYf_angle_d1.14120580
ELECTRON MICROSCOPYf_dihedral_angle_d5.5762004
ELECTRON MICROSCOPYf_chiral_restr0.0722286
ELECTRON MICROSCOPYf_plane_restr0.0062628

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