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- PDB-7fjf: Cryo-EM structure of a membrane protein(CS) -

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Basic information

Entry
Database: PDB / ID: 7fjf
TitleCryo-EM structure of a membrane protein(CS)
Components
  • (T cell receptor ...) x 2
  • (T-cell surface glycoprotein CD3 ...) x 4
KeywordsIMMUNE SYSTEM / membrane / immune
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 / Fc-gamma receptor signaling pathway / T cell activation involved in immune response / CD4-positive, alpha-beta T cell proliferation / gamma-delta T cell activation ...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 / Fc-gamma receptor signaling pathway / T cell activation involved in immune response / CD4-positive, alpha-beta T cell proliferation / gamma-delta T cell activation / negative thymic T cell selection / positive regulation of CD4-positive, alpha-beta T cell proliferation / 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 receptor complex / smoothened signaling pathway / establishment or maintenance of cell polarity / positive regulation of interleukin-4 production / dendrite development / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / alpha-beta T cell activation / Generation of second messenger molecules / immunological synapse / FCGR activation / PD-1 signaling / Role of phospholipids in phagocytosis / positive regulation of calcium-mediated signaling / T cell receptor binding / negative regulation of smoothened signaling pathway / positive regulation of T cell proliferation / immunoglobulin complex, circulating / immunoglobulin receptor binding / cell surface receptor protein tyrosine kinase signaling pathway / T cell costimulation / positive regulation of interleukin-2 production / T cell activation / cerebellum development / FCGR3A-mediated IL10 synthesis / protein tyrosine kinase binding / complement activation, classical pathway / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / antigen binding / response to bacterium / clathrin-coated endocytic vesicle membrane / Regulation of actin dynamics for phagocytic cup formation / SH3 domain binding / transmembrane signaling receptor activity / peptide antigen binding / positive regulation of peptidyl-tyrosine phosphorylation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / positive regulation of type II interferon production / cell-cell junction / signaling receptor complex adaptor activity / protein transport / Cargo recognition for clathrin-mediated endocytosis / Downstream TCR signaling / protein complex oligomerization / Clathrin-mediated endocytosis / T cell receptor signaling pathway / cell body / antibacterial humoral response / protein-containing complex assembly / regulation of apoptotic process / adaptive immune response / dendritic spine / cell surface receptor signaling pathway / blood microparticle / G protein-coupled receptor signaling pathway / protein heterodimerization activity / external side of plasma membrane / negative regulation of gene expression / positive regulation of gene expression / protein kinase binding / Golgi apparatus / cell surface / endoplasmic reticulum / protein homodimerization activity / extracellular exosome / identical protein binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
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. ...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 / T-cell receptor alpha chain, constant domain / Domain of unknown function (DUF1968) / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / 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
CHOLEST-5-EN-3-YL HYDROGEN SULFATE / T cell receptor alpha variable 12-3 / T cell receptor beta constant 2 / T cell receptor beta variable 6-5 / Possible J 11 gene segment / T cell receptor alpha chain constant / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 epsilon chain / T-cell surface glycoprotein CD3 gamma chain / M1-specific T cell receptor beta chain / T-cell surface glycoprotein CD3 zeta chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsChen, Y. / Zhu, Y. / Gao, W. / Zhang, A. / Guo, C. / Huang, Z.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31825008 China
CitationJournal: Mol Cell / Year: 2022
Title: Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.
Authors: Yan Chen / Yuwei Zhu / Xiang Li / Wenbo Gao / Ziqi Zhen / De Dong / Buliao Huang / Zhuo Ma / Anqi Zhang / Xiaocui Song / Yan Ma / Changyou Guo / Fan Zhang / Zhiwei Huang /
Abstract: Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms ...Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3ζ into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3ζ transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex.
History
DepositionAug 3, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
b: T-cell surface glycoprotein CD3 zeta chain
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
m: T cell receptor alpha variable 12-3,Possible J 11 gene segment,T cell receptor alpha chain constant
n: T cell receptor beta variable 6-5,M1-specific T cell receptor beta chain,T cell receptor beta constant 2
a: T-cell surface glycoprotein CD3 zeta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)189,72410
Polymers188,7908
Non-polymers9332
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 18810.520 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
#2: Protein T-cell surface glycoprotein CD3 delta chain / T-cell receptor T3 delta chain


Mass: 18949.537 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
#3: Protein T-cell surface glycoprotein CD3 epsilon chain / T-cell surface antigen T3/Leu-4 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, T3E / Production host: Homo sapiens (human) / References: UniProt: P07766
#4: Protein T-cell surface glycoprotein CD3 gamma chain / T-cell receptor T3 gamma chain


Mass: 20493.457 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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T cell receptor ... , 2 types, 2 molecules mn

#5: Protein T cell receptor alpha variable 12-3,Possible J 11 gene segment,T cell receptor alpha chain constant


Mass: 30763.717 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRAV12-3, Tcr-alpha, TRAC, TCRA / Production host: Homo sapiens (human)
References: UniProt: A0A0B4J271, UniProt: A0N4Z6, UniProt: P01848
#6: Protein T cell receptor beta variable 6-5,M1-specific T cell receptor beta chain,T cell receptor beta constant 2


Mass: 34614.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRBV6-5, TRB, TRBC2 / Production host: Homo sapiens (human)
References: UniProt: A0A0K0K1A5, UniProt: P0DSE2, UniProt: A0A0G2JMB4

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Non-polymers , 1 types, 2 molecules

#7: Chemical ChemComp-C3S / CHOLEST-5-EN-3-YL HYDROGEN SULFATE / CHOLESTEROL-SULFATE


Mass: 466.717 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O4S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: immune system / Type: COMPLEX / Entity ID: #1-#6 / 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: NITROGEN

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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: 60 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1028575 / Symmetry type: POINT

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