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- PDB-9c3e: TCR - CD3 complex bound to HLA -

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Basic information

Entry
Database: PDB / ID: 9c3e
TitleTCR - CD3 complex bound to HLA
Components
  • (T-cell surface glycoprotein CD3 ...) x 4
  • Cancer/testis antigen 1,Beta-2-microglobulin,MHC class I antigen
  • TCRa
  • TCRb (EGFP fusion)
KeywordsIMMUNE SYSTEM / T-cell receptor / TCR / 1G4 / nanodisc / CD3 / HLA / NY-ESO-1
Function / homology
Function and homology information


tRNA threonylcarbamoyladenosine metabolic process / 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 ...tRNA threonylcarbamoyladenosine metabolic process / 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 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 / negative regulation of receptor binding / T cell activation / early endosome lumen / cerebellum development / 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 / ER to Golgi transport vesicle membrane / calcium-mediated signaling / 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 / 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 / Downstream TCR signaling
Similarity search - Function
CTAG/Pcc1 family / Transcription factor Pcc1 / 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 ...CTAG/Pcc1 family / Transcription factor Pcc1 / 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, 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
CHOLESTEROL / MHC class I antigen / 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 / Beta-2-microglobulin / Cancer/testis antigen 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsNotti, R.Q. / Walz, T.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)T32CA9207 United States
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)KL2TR001865 United States
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)UL1TR001866 United States
Other privateBlack Family Metastasis Center
Shapiro-Silverberg Fund for the Advancement of Translational Research United States
The Mark FoundationWalz-Notti Aspire United States
CitationJournal: bioRxiv / Year: 2024
Title: The resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex.
Authors: Ryan Q Notti / Fei Yi / Søren Heissel / Martin W Bush / Zaki Molvi / Pujita Das / Henrik Molina / Christopher A Klebanoff / Thomas Walz
Abstract: The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte ...The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the "open and extended" conformation seen in detergent( ), the unliganded TCR-CD3 in nanodiscs adopts two related "closed and compacted" conformations that represent its physiologic resting state . By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. Together, these results reveal allosteric conformational change during TCR activation and highlight the importance of native-like lipid environments for membrane protein structure determination.
History
DepositionMay 31, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 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: TCRa
B: TCRb (EGFP fusion)
D: T-cell surface glycoprotein CD3 delta chain
E: T-cell surface glycoprotein CD3 epsilon chain
F: T-cell surface glycoprotein CD3 epsilon chain
G: T-cell surface glycoprotein CD3 gamma chain
X: T-cell surface glycoprotein CD3 zeta chain
Y: T-cell surface glycoprotein CD3 zeta chain
H: Cancer/testis antigen 1,Beta-2-microglobulin,MHC class I antigen
hetero molecules


Theoretical massNumber of molelcules
Total (without water)277,35920
Polymers274,2309
Non-polymers3,13011
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules ABH

#1: Protein TCRa


Mass: 30214.033 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Protein TCRb (EGFP fusion)


Mass: 62121.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#7: Protein Cancer/testis antigen 1,Beta-2-microglobulin,MHC class I antigen / Autoimmunogenic cancer/testis antigen NY-ESO-1 / Cancer/testis antigen 6.1 / CT6.1 / L antigen ...Autoimmunogenic cancer/testis antigen NY-ESO-1 / Cancer/testis antigen 6.1 / CT6.1 / L antigen family member 2 / LAGE-2


Mass: 62221.281 Da / Num. of mol.: 1 / Mutation: C9V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: CTAG1A, CTAG, CTAG1, ESO1, LAGE2, LAGE2A, CTAG1B, LAGE2B, B2M, CDABP0092, HDCMA22P, HLA-A
Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P78358, UniProt: P61769, UniProt: H9BNV4

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

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


Mass: 13836.026 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3D, T3D / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P04234
#4: Protein T-cell surface glycoprotein CD3 epsilon chain


Mass: 23174.227 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3E / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P07766
#5: Protein T-cell surface glycoprotein CD3 gamma chain / T-cell receptor T3 gamma chain


Mass: 22041.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD3G, T3G / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P09693
#6: Protein T-cell surface glycoprotein CD3 zeta chain / T-cell receptor T3 zeta chain


Mass: 18723.439 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD247, CD3Z, T3Z, TCRZ / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P20963

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Sugars , 2 types, 9 molecules

#8: 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: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#9: 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.: 8 / 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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Non-polymers , 1 types, 2 molecules

#10: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY
Sequence detailsThe authors state that the fusion protein was provided by a commercial supplier. The linker lengths ...The authors state that the fusion protein was provided by a commercial supplier. The linker lengths and sequences are unknown.

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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: TCR - CD3 complex in nanodisc bound to NY-ESO-1, B2M, HLA-A*02:01 single chain trimer
Type: COMPLEX / Entity ID: #1-#7 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293F
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaCl1
225 mMHEPES1
SpecimenConc.: 0.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 magnification: 64000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 0 mm
Image recordingElectron dose: 51 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21_5207: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00511230
ELECTRON MICROSCOPYf_angle_d0.88715288
ELECTRON MICROSCOPYf_dihedral_angle_d9.2221904
ELECTRON MICROSCOPYf_chiral_restr0.051757
ELECTRON MICROSCOPYf_plane_restr0.0051923

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