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Entry
Database: PDB / ID: 7phr
TitleStructure of a fully assembled T-cell receptor engaging a tumor-associated peptide-MHC I
Components
  • (T-cell receptor ...) x 2
  • (T-cell surface glycoprotein CD3 ...) x 4
  • Beta-2-microglobulin
  • HLA class I histocompatibility antigen, A alpha chain
  • Tumor-associated antigentic peptide gp100
KeywordsIMMUNE SYSTEM / T-cell receptor / TCR / Major Histocompatibility Complex / MHC / Antigen / Adaptive Immunity / Cancer / Complex
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 T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / cis-Golgi network membrane / positive regulation of melanin biosynthetic process / Fc-gamma receptor signaling pathway / CD4-positive, alpha-beta T cell proliferation ...regulation of lymphocyte apoptotic process / gamma-delta T cell receptor complex / Fc-gamma receptor III complex / T cell anergy / positive regulation of T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / cis-Golgi network membrane / positive regulation of melanin biosynthetic process / Fc-gamma receptor signaling pathway / CD4-positive, alpha-beta T cell proliferation / gamma-delta T cell activation / negative thymic T cell selection / melanin biosynthetic process / melanosome membrane / multivesicular body, internal vesicle / melanosome organization / positive regulation of CD4-positive, alpha-beta T cell proliferation / multivesicular body membrane / alpha-beta T cell receptor complex / positive regulation of protein localization to cell surface / positive thymic T cell selection / signal complex assembly / Nef and signal transduction / positive regulation of cell-matrix adhesion / T cell mediated cytotoxicity directed against tumor cell target / T cell receptor complex / positive regulation of memory T cell activation / TAP complex binding / smoothened signaling pathway / establishment or maintenance of cell polarity / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell proliferation / positive regulation of interleukin-4 production / CD8 receptor binding / dendrite development / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / antigen processing and presentation of exogenous peptide antigen via MHC class I / endoplasmic reticulum exit site / alpha-beta T cell activation / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / Generation of second messenger molecules / immunological synapse / TAP binding / FCGR activation / protection from natural killer cell mediated cytotoxicity / PD-1 signaling / Role of phospholipids in phagocytosis / beta-2-microglobulin binding / positive regulation of calcium-mediated signaling / T cell receptor binding / negative regulation of smoothened signaling pathway / detection of bacterium / positive regulation of T cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / T cell costimulation / positive regulation of interleukin-2 production / T cell activation / bioluminescence / cerebellum development / FCGR3A-mediated IL10 synthesis / protein tyrosine kinase binding / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / generation of precursor metabolites and energy / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / calcium-mediated signaling / lumenal side of endoplasmic reticulum membrane / cellular response to iron ion / Endosomal/Vacuolar pathway / apoptotic signaling pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / FCGR3A-mediated phagocytosis / cellular response to iron(III) ion / clathrin-coated endocytic vesicle membrane / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / negative regulation of forebrain neuron differentiation / regulation of erythrocyte differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of iron ion transport / response to molecule of bacterial origin / MHC class I peptide loading complex / HFE-transferrin receptor complex / T cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / Regulation of actin dynamics for phagocytic cup formation / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / negative regulation of neurogenesis / SH3 domain binding
Similarity search - Function
PKD- and KLD-Associated Transmembrane / PKAT, KLD domain / PKAT, KLD domain / PKD domain / CD3 gamma/delta subunit, Ig-like domain / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 zeta subunit / T-cell surface glycoprotein CD3 zeta subunit/High affinity IgE receptor gamma subunit / T-cell surface glycoprotein CD3 zeta chain / Ig-like domain on T-cell surface glycoprotein CD3 epsilon chain ...PKD- and KLD-Associated Transmembrane / PKAT, KLD domain / PKAT, KLD domain / PKD domain / CD3 gamma/delta subunit, Ig-like domain / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 zeta subunit / T-cell surface glycoprotein CD3 zeta subunit/High affinity IgE receptor gamma subunit / T-cell surface glycoprotein CD3 zeta chain / Ig-like domain on T-cell surface glycoprotein CD3 epsilon chain / CD3 protein, epsilon/gamma/delta subunit / Immunoreceptor tyrosine-based activation motif / Phosphorylated immunoreceptor signalling ITAM / ITAM motif mammalian type profile. / Immunoreceptor tyrosine-based activation motif / Polycystic kidney disease (PKD) domain profile. / PKD domain / PKD domain superfamily / PKD/Chitinase domain / Repeats in polycystic kidney disease 1 (PKD1) and other proteins / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Immunoglobulin subtype 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
Similarity search - Domain/homology
T-cell surface glycoprotein CD3 delta chain / HLA class I histocompatibility antigen, A alpha chain / T-cell surface glycoprotein CD3 epsilon chain / T-cell surface glycoprotein CD3 gamma chain / T-cell surface glycoprotein CD3 zeta chain / Melanocyte protein PMEL / Green fluorescent protein / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsSusac, L. / Thomas, C. / Tampe, R.
Funding support Germany, 4items
OrganizationGrant numberCountry
German Research Foundation (DFG)CRC 807/P16 No. 57566863 Germany
German Research Foundation (DFG)TA157/12-1 Germany
European Research Council (ERC)Advanced Grant No. 789121 Germany
Wellcome Trust207547/Z/17/Z Germany
CitationJournal: Cell / Year: 2022
Title: Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC.
Authors: Lukas Sušac / Mai T Vuong / Christoph Thomas / Sören von Bülow / Caitlin O'Brien-Ball / Ana Mafalda Santos / Ricardo A Fernandes / Gerhard Hummer / Robert Tampé / Simon J Davis /
Abstract: The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the ...The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCRαβ/CD3δγεζ complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements.
History
DepositionAug 18, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: T-cell receptor alpha chain
B: T-cell receptor beta chain
C: T-cell surface glycoprotein CD3 gamma chain
D: T-cell surface glycoprotein CD3 delta chain, green fluorescent protein
E: T-cell surface glycoprotein CD3 epsilon chain
H: HLA class I histocompatibility antigen, A alpha chain
L: Beta-2-microglobulin
P: Tumor-associated antigentic peptide gp100
Z: T-cell surface glycoprotein CD3 zeta chain
e: T-cell surface glycoprotein CD3 epsilon chain
z: T-cell surface glycoprotein CD3 zeta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,50317
Polymers201,17611
Non-polymers1,3276
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, gel filtration, native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area34150 Å2
ΔGint-182 kcal/mol
Surface area65060 Å2
MethodPISA

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Components

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T-cell receptor ... , 2 types, 2 molecules AB

#1: Protein T-cell receptor alpha chain


Mass: 27979.268 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Protein T-cell receptor beta chain


Mass: 32750.736 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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

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


Mass: 13713.741 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3G, T3G / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P09693
#4: Protein T-cell surface glycoprotein CD3 delta chain, green fluorescent protein / T-cell receptor T3 delta chain


Mass: 39858.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Aequorea victoria (jellyfish)
Gene: CD3D, T3D, GFP / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P04234, UniProt: P42212
#5: Protein T-cell surface glycoprotein CD3 epsilon chain / T-cell surface antigen T3/Leu-4 epsilon chain


Mass: 15316.222 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3E, T3E / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P07766
#9: Protein/peptide T-cell surface glycoprotein CD3 zeta chain / T-cell receptor T3 zeta chain


Mass: 4138.015 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: Cricetulus griseus (Chinese hamster) / References: UniProt: P20963

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Protein , 2 types, 2 molecules HL

#6: Protein HLA class I histocompatibility antigen, A alpha chain / Human leukocyte antigen A / HLA-A


Mass: 35054.613 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A, HLAA / Production host: Escherichia coli (E. coli) / References: UniProt: P04439
#7: Protein Beta-2-microglobulin


Mass: 11936.408 Da / Num. of mol.: 1
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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Protein/peptide / Sugars , 2 types, 7 molecules P

#10: 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
#8: Protein/peptide Tumor-associated antigentic peptide gp100 / ME20-M / ME20M / Melanocyte protein Pmel 17 / Melanocytes lineage-specific antigen GP100 / Melanoma- ...ME20-M / ME20M / Melanocyte protein Pmel 17 / Melanocytes lineage-specific antigen GP100 / Melanoma-associated ME20 antigen / P1 / P100 / Premelanosome protein / Silver locus protein homolog / Melanocyte protein PMEL


Mass: 974.107 Da / Num. of mol.: 1 / Mutation: A9V / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P40967

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Details

Has ligand of interestN

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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: Fully assembled T-cell receptor engaging a tumor-associated peptide-MHC I
Type: COMPLEX / Entity ID: #1-#9 / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Aequorea victoria (jellyfish)6100
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Cricetulus griseus (Chinese hamster)10029
21Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
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
Image recordingElectron dose: 61 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154408 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00611778
ELECTRON MICROSCOPYf_angle_d0.76815989
ELECTRON MICROSCOPYf_dihedral_angle_d12.5454261
ELECTRON MICROSCOPYf_chiral_restr0.051774
ELECTRON MICROSCOPYf_plane_restr0.0042045

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