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- EMDB-61741: Structure of interleukin receptor common gamma chain (IL2Rgamma/C... -

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Basic information

Entry
Database: EMDB / ID: EMD-61741
TitleStructure of interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
Map data
Sample
  • Complex: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
    • Protein or peptide: Cytokine receptor common subunit gamma
    • Protein or peptide: 2D4-Heavy Chain
    • Protein or peptide: 2D4-Light Chain
    • Protein or peptide: Anti-Fab nanobody
KeywordsIL2Rg / CD132 / IL-2 / 2D4 / MEMBRANE PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsLu QJ / Yin HQ
Funding support China, 2 items
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, 2024-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateDec 18, 2024-
Current statusDec 18, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61741.png

Downloads & links

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Map

FileDownload / File: emd_61741.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.72 Å/pix.
x 320 pix.
= 231.04 Å		0.72 Å/pix.
x 320 pix.
= 231.04 Å		0.72 Å/pix.
x 320 pix.
= 231.04 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.722 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.6234499 - 0.7781425
Average (Standard dev.)0.00001483193 (±0.013753023)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 231.04001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_61741_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #2

Fileemd_61741_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61741_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Interleukin receptor common gamma chain (IL2Rgamma/CD132) in comp...

EntireName: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
Components
  • Complex: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
    • Protein or peptide: Cytokine receptor common subunit gamma
    • Protein or peptide: 2D4-Heavy Chain
    • Protein or peptide: 2D4-Light Chain
    • Protein or peptide: Anti-Fab nanobody

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Supramolecule #1: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in comp...

SupramoleculeName: Interleukin receptor common gamma chain (IL2Rgamma/CD132) in complex with 2D4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cytokine receptor common subunit gamma

MacromoleculeName: Cytokine receptor common subunit gamma / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.301557 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: LNTTILTPNG NEDTTADFFL TTMPTDSLSV STLPLPEVQC FVFNVEYMNC TWNSSSEPQP TNLTLHYWYK NSDNDKVQKC SHYLFSEEI TSGCQLQKKE IHLYQTFVVQ LQDPREPRRQ ATQMLKLQNL VIPWAPENLT LHKLSESQLE LNWNNRFLNH C LEHLVQYR ...String:
LNTTILTPNG NEDTTADFFL TTMPTDSLSV STLPLPEVQC FVFNVEYMNC TWNSSSEPQP TNLTLHYWYK NSDNDKVQKC SHYLFSEEI TSGCQLQKKE IHLYQTFVVQ LQDPREPRRQ ATQMLKLQNL VIPWAPENLT LHKLSESQLE LNWNNRFLNH C LEHLVQYR TDWDHSWTEQ SVDYRHKFSL PSVDGQKRYT FRVRSRFNPL CGSAQHWSEW SHPIHWGSNT SKENPFLFAL EA

UniProtKB: Cytokine receptor common subunit gamma

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Macromolecule #2: 2D4-Heavy Chain

MacromoleculeName: 2D4-Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.049832 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGSSVKV SCKTSGFNIE DIYLHWVRQA PGQGLEWMGR IDPANGKSNY DPKFQGRVTI TADTSTSTAY MELSSLRSE DTAVYYCAAL RFFGLDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN S GALTSGVH ...String:
QVQLVQSGAE VKKPGSSVKV SCKTSGFNIE DIYLHWVRQA PGQGLEWMGR IDPANGKSNY DPKFQGRVTI TADTSTSTAY MELSSLRSE DTAVYYCAAL RFFGLDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN S GALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY TCNVDHKPSN TKVDKRV

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Macromolecule #3: 2D4-Light Chain

MacromoleculeName: 2D4-Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.347873 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVLTQSPAT LSLSPGERAT LSCRATSSVS YMYWYQQKPG QAPELLIYRT SNLASGIPAR FSGSGSGTDY TLTISSLEPE DFAVYYCQQ WSSNPPTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
EIVLTQSPAT LSLSPGERAT LSCRATSSVS YMYWYQQKPG QAPELLIYRT SNLASGIPAR FSGSGSGTDY TLTISSLEPE DFAVYYCQQ WSSNPPTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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Macromolecule #4: Anti-Fab nanobody

MacromoleculeName: Anti-Fab nanobody / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.219525 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSQVQLQESG GGLVQPGGSL RLSCAASGRT ISRYAMSWFR QAPGKEREFV AVARRSGDGA FYADSVQGRF TVSRDDAKNT VYLQMNSLK PEDTAVYYCA IDSDTFYSGS YDYWGQGTQV TVSSHHHHHH

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 354578
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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