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- PDB-8es9: CryoEM structure of PN45428 TCR-CD3 in complex with HLA-A2 MAGEA4 -

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Entry
Database: PDB / ID: 8es9
TitleCryoEM structure of PN45428 TCR-CD3 in complex with HLA-A2 MAGEA4
Components
  • (T-cell surface glycoprotein CD3 ...) x 4
  • Beta-2-microglobulin
  • MHC class I antigen
  • Melanoma-associated antigen 4
  • PN45428 TCR alpha chain
  • PN45428 TCR beta chain
KeywordsIMMUNE SYSTEM / TCR / receptor / membrane protein / CD3 / MHC / HLA
Function / homology
Function and homology information


regulation of lymphocyte apoptotic process / gamma-delta T cell receptor complex / Fc-gamma receptor III complex / T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / positive regulation of T cell anergy / Fc-gamma receptor signaling pathway / gamma-delta T cell activation / CD4-positive, alpha-beta T cell proliferation / negative thymic T cell selection ...regulation of lymphocyte apoptotic process / gamma-delta T cell receptor complex / Fc-gamma receptor III complex / T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / positive regulation of T cell anergy / Fc-gamma receptor signaling pathway / gamma-delta T cell activation / CD4-positive, alpha-beta T cell proliferation / negative thymic T cell selection / positive regulation of CD4-positive, alpha-beta T cell proliferation / alpha-beta T cell receptor complex / positive thymic T cell selection / positive regulation of protein localization to cell surface / signal complex assembly / Nef and signal transduction / positive regulation of cell-matrix adhesion / T cell receptor complex / smoothened signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / positive regulation of interleukin-4 production / establishment or maintenance of cell polarity / antigen processing and presentation of peptide antigen via MHC class I / dendrite development / protein complex oligomerization / alpha-beta T cell activation / Generation of second messenger molecules / FCGR activation / immunological synapse / Co-inhibition by PD-1 / Role of phospholipids in phagocytosis / T cell receptor binding / T cell costimulation / positive regulation of cell cycle / positive regulation of T cell proliferation / positive regulation of interleukin-2 production / positive regulation of calcium-mediated signaling / FCGR3A-mediated IL10 synthesis / cell surface receptor protein tyrosine kinase signaling pathway / protein tyrosine kinase binding / T cell activation / negative regulation of receptor binding / cerebellum development / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / transferrin transport / cellular response to iron ion / lumenal side of endoplasmic reticulum membrane / Endosomal/Vacuolar pathway / negative regulation of smoothened signaling pathway / FCGR3A-mediated phagocytosis / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide antigen assembly with MHC class II protein complex / apoptotic signaling pathway / cellular response to iron(III) ion / MHC class II protein complex / negative regulation of forebrain neuron differentiation / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / clathrin-coated endocytic vesicle membrane / calcium-mediated signaling / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of iron ion transport / regulation of erythrocyte differentiation / HFE-transferrin receptor complex / response to molecule of bacterial origin / MHC class I peptide loading complex / T cell mediated cytotoxicity / positive regulation of T cell cytokine production / antigen processing and presentation of endogenous peptide antigen via MHC class I / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of immune response / MHC class I protein complex / positive regulation of T cell activation / peptide antigen binding / positive regulation of receptor-mediated endocytosis / Regulation of actin dynamics for phagocytic cup formation / negative regulation of neurogenesis / SH3 domain binding / cellular response to nicotine / positive regulation of T cell mediated cytotoxicity / multicellular organismal-level iron ion homeostasis / histone deacetylase binding / specific granule lumen / positive regulation of type II interferon production / phagocytic vesicle membrane / recycling endosome membrane / Interferon gamma signaling / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / negative regulation of epithelial cell proliferation / MHC class II protein complex binding / Modulation by Mtb of host immune system / cell-cell junction / late endosome membrane / sensory perception of smell / positive regulation of cellular senescence / transmembrane signaling receptor activity / tertiary granule lumen
Similarity search - Function
Melanoma associated antigen, N-terminal / Melanoma associated antigen family N terminal / Melanoma associated antigen family N terminal / MAGE conserved domain profile. / MAGE homology domain / Melanoma-associated antigen / MAGE homology domain, winged helix WH1 motif / MAGE homology domain, winged helix WH2 motif / MAGE homology domain / Melanoma-associated antigen ...Melanoma associated antigen, N-terminal / Melanoma associated antigen family N terminal / Melanoma associated antigen family N terminal / MAGE conserved domain profile. / MAGE homology domain / Melanoma-associated antigen / MAGE homology domain, winged helix WH1 motif / MAGE homology domain, winged helix WH2 motif / MAGE homology domain / Melanoma-associated antigen / T-cell surface glycoprotein CD3 zeta subunit / CD3 gamma/delta subunit, Ig-like domain / T-cell surface glycoprotein CD3 delta chain / Ig-like domain on T-cell surface glycoprotein CD3 epsilon chain / CD3 protein, epsilon/gamma/delta subunit / T-cell surface glycoprotein CD3 zeta subunit/High affinity IgE receptor gamma subunit / T-cell surface glycoprotein CD3 zeta chain / Immunoreceptor tyrosine-based activation motif / Phosphorylated immunoreceptor signalling ITAM / ITAM motif mammalian type profile. / Immunoreceptor tyrosine-based activation motif / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / MHC class I alpha chain, alpha1 alpha2 domains / Immunoglobulin subtype 2 / Class I Histocompatibility antigen, domains alpha 1 and 2 / Immunoglobulin C-2 Type / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL HEMISUCCINATE / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 epsilon chain / T-cell surface glycoprotein CD3 gamma chain / T-cell surface glycoprotein CD3 zeta chain / Melanoma-associated antigen 4 / Beta-2-microglobulin / MHC class I antigen
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsSaotome, K. / Franklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Commun / Year: 2023
Title: Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM.
Authors: Kei Saotome / Drew Dudgeon / Kiersten Colotti / Michael J Moore / Jennifer Jones / Yi Zhou / Ashique Rafique / George D Yancopoulos / Andrew J Murphy / John C Lin / William C Olson / Matthew C Franklin /
Abstract: The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity ...The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity of TCR-pMHC interactions and informing the development of therapeutics. Despite the rapid rise of single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained the preferred method for structure determination of TCR-pMHC complexes. Here, we report cryoEM structures of two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, the cancer-testis antigen HLA-A2/MAGEA4 (230-239). We also determined cryoEM structures of pMHCs containing MAGEA4 (230-239) peptide and the closely related MAGEA8 (232-241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions.
History
DepositionOct 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PN45428 TCR alpha chain
B: PN45428 TCR beta chain
Z: T-cell surface glycoprotein CD3 zeta chain
Y: T-cell surface glycoprotein CD3 zeta chain
D: T-cell surface glycoprotein CD3 delta chain
F: T-cell surface glycoprotein CD3 epsilon chain
G: T-cell surface glycoprotein CD3 gamma chain
E: T-cell surface glycoprotein CD3 epsilon chain
N: MHC class I antigen
M: Beta-2-microglobulin
P: Melanoma-associated antigen 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,26721
Polymers237,01811
Non-polymers3,24910
Water00
1


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

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Components

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Protein , 4 types, 4 molecules ABNM

#1: Protein PN45428 TCR alpha chain


Mass: 30415.229 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Protein PN45428 TCR beta chain


Mass: 35487.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#7: Protein MHC class I antigen


Mass: 32082.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A*02:01 / Production host: Escherichia coli (E. coli) / References: UniProt: Q861F7
#8: Protein Beta-2-microglobulin


Mass: 11879.356 Da / Num. of mol.: 1 / Fragment: UNP residues 21-119
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Escherichia coli (E. coli) / References: UniProt: P61769

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T-cell surface glycoprotein CD3 ... , 4 types, 6 molecules ZYDFEG

#3: Protein T-cell surface glycoprotein CD3 zeta chain / T-cell receptor T3 zeta chain


Mass: 19654.486 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD247, CD3Z, T3Z, TCRZ / Production host: Homo sapiens (human) / References: UniProt: P20963
#4: Protein T-cell surface glycoprotein CD3 delta chain / T-cell receptor T3 delta chain


Mass: 19150.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3D, T3D / Production host: Homo sapiens (human) / References: UniProt: P04234
#5: Protein T-cell surface glycoprotein CD3 epsilon chain / T-cell surface antigen T3/Leu-4 epsilon chain


Mass: 23432.459 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3E, T3E / Production host: Homo sapiens (human) / References: UniProt: P07766
#6: Protein T-cell surface glycoprotein CD3 gamma chain / T-cell receptor T3 gamma chain


Mass: 20694.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3G, T3G / Production host: Homo sapiens (human) / References: UniProt: P09693

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Protein/peptide / Non-polymers , 2 types, 2 molecules P

#13: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#9: Protein/peptide Melanoma-associated antigen 4 / Cancer/testis antigen 1.4 / CT1.4 / MAGE-4 antigen / MAGE-41 antigen / MAGE-X2 antigen


Mass: 1134.200 Da / Num. of mol.: 1 / Fragment: peptide (UNP residues 230-239) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P43358

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Sugars , 3 types, 9 molecules

#10: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#11: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#12: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: PN45428 TCR-CD3 complex bound to HLA-A2 MAGEA4 (230-239) in the presence of 2M2 Fab
Type: COMPLEX / Entity ID: #1-#9 / Source: RECOMBINANT
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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107308 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 85.59 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004112118
ELECTRON MICROSCOPYf_angle_d0.652816438
ELECTRON MICROSCOPYf_chiral_restr0.04891844
ELECTRON MICROSCOPYf_plane_restr0.00372083
ELECTRON MICROSCOPYf_dihedral_angle_d6.3351679

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