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- PDB-9jqt: Structure of interleukin receptor common gamma chain (IL2Rgamma/C... -

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Basic information

Entry
Database: PDB / ID: 9jqt
TitleStructure of interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
Components
  • 2D4-Heavy Chain
  • 2D4-Light Chain
  • Anti-Fab nanobody
  • Cytokine receptor common subunit gamma
KeywordsMEMBRANE PROTEIN / IL2Rg / CD132 / IL-2 / 2D4
Function / homology
Function and homology information


mature B cell differentiation / interleukin-15 receptor activity / interleukin-2 binding / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / positive regulation of T cell differentiation in thymus / lymphocyte differentiation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway ...mature B cell differentiation / interleukin-15 receptor activity / interleukin-2 binding / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / positive regulation of T cell differentiation in thymus / lymphocyte differentiation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / cellular homeostasis / STAT3 nuclear events downstream of ALK signaling / Interleukin-15 signaling / cytokine receptor activity / Interleukin-2 signaling / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / cytokine binding / Interleukin receptor SHC signaling / coreceptor activity / positive regulation of phagocytosis / Interleukin-7 signaling / cytokine-mediated signaling pathway / T cell differentiation in thymus / RAF/MAP kinase cascade / Interleukin-4 and Interleukin-13 signaling / gene expression / receptor complex / endosome / immune response / external side of plasma membrane / cell surface / signal transduction / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
: / : / Cytokine receptor-like factor 2-like, D2 domain / Cytokine receptor-like factor 2, domain 1 / Short hematopoietin receptor family 1 signature. / Short hematopoietin receptor, family 1, conserved site / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Cytokine receptor common subunit gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsLu, Q.J. / Yin, H.Q.
Funding support China, 2items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)NO. 32141004 China
Ministry of Science and Technology (MoST, China)No. 2022YFC3601800 China
CitationJournal: Signal Transduct Target Ther / Year: 2024
Title: 2D4, a humanized monoclonal antibody targeting CD132, is a promising treatment for systemic lupus erythematosus.
Authors: Huiqi Yin / Liming Li / Xiwei Feng / Zijun Wang / Meiling Zheng / Junpeng Zhao / Xinyu Fan / Wei Wu / Lingyu Gao / Yijing Zhan / Ming Zhao / Qianjin Lu /
Abstract: Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to ...Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to six inflammatory factor receptors implicated in SLE. Our study revealed heightened CD132 expression in SLE patients' lymphocytes, contributing to the production of pro-inflammatory cytokines and immunoglobulins. We developed a novel humanized anti-CD132 monoclonal antibody, named as 2D4. 2D4 efficiently blocked IL-21 and IL-15, with limited effectiveness against IL-2, thereby suppressing T and B cells without disrupting immune tolerance. In the mouse immunization model, 2D4 virtually inhibited T cell-dependent, antigen-specific B-cell response. In lupus murine models, 2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers, also diminishing proteinuria and glomerulonephritis. Compared to Belimumab, 2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function. Moreover, 2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE, highlighting its therapeutic potential for SLE individuals. Potent, 2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders.
History
DepositionSep 28, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytokine receptor common subunit gamma
B: 2D4-Heavy Chain
C: 2D4-Light Chain
D: Anti-Fab nanobody


Theoretical massNumber of molelcules
Total (without water)88,9194
Polymers88,9194
Non-polymers00
Water00
1


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

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Components

#1: Protein Cytokine receptor common subunit gamma / Interleukin-2 receptor subunit gamma / IL-2 receptor subunit gamma / IL-2R subunit gamma / IL-2RG / ...Interleukin-2 receptor subunit gamma / IL-2 receptor subunit gamma / IL-2R subunit gamma / IL-2RG / gammaC / p64


Mass: 28301.557 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL2RG / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P31785
#2: Antibody 2D4-Heavy Chain


Mass: 23049.832 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)
#3: Antibody 2D4-Light Chain


Mass: 23347.873 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)
#4: Antibody Anti-Fab nanobody


Mass: 14219.525 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
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: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV
Image scansWidth: 4096 / Height: 4096

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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: 354578 / Symmetry type: POINT

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