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- EMDB-28523: Structure of interleukin receptor common gamma chain (IL2Rgamma) ... -

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Basic information

Entry
Database: EMDB / ID: EMD-28523
TitleStructure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Map dataStructure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Sample
  • Complex: Complex of IL2Rgamma extracellular domain with Fab fragments of antibodies REGN7257 and REGN9432
    • Protein or peptide: Cytokine receptor common subunit gamma
    • Protein or peptide: REGN7257 Fab heavy chain
    • Protein or peptide: REGN7257 Fab light chain
    • Protein or peptide: REGN9432 Fab heavy chain
    • Protein or peptide: REGN9432 Fab light chain
Function / homology
Function and homology information


interleukin-7-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 / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway ...interleukin-7-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 / Interleukin-9 signaling / Interleukin-21 signaling / 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 / STAT3 nuclear events downstream of ALK signaling / Interleukin-15 signaling / Interleukin-2 signaling / cytokine receptor activity / positive regulation of B cell differentiation / cytokine binding / Interleukin receptor SHC signaling / coreceptor activity / positive regulation of phagocytosis / Interleukin-7 signaling / cytokine-mediated signaling pathway / gene expression / T cell differentiation in thymus / RAF/MAP kinase cascade / Interleukin-4 and Interleukin-13 signaling / receptor complex / endosome / immune response / external side of plasma membrane / positive regulation of gene expression / cell surface / endoplasmic reticulum / signal transduction / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
: / : / Cytokine receptor-like factor 2-like, D1 domain / Cytokine receptor-like factor 2-like, D2 domain / 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 speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsFranklin MC / Romero Hernandez A
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Sci Transl Med / Year: 2023
Title: Blocking common γ chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models.
Authors: Audrey Le Floc'h / Kirsten Nagashima / Dylan Birchard / George Scott / Li-Hong Ben / Dharani Ajithdoss / Kaitlyn Gayvert / Annabel Romero Hernandez / Olivier Herbin / Amanda Tay / Pamela ...Authors: Audrey Le Floc'h / Kirsten Nagashima / Dylan Birchard / George Scott / Li-Hong Ben / Dharani Ajithdoss / Kaitlyn Gayvert / Annabel Romero Hernandez / Olivier Herbin / Amanda Tay / Pamela Farrales / Chandrashekhar K Korgaonkar / Hao Pan / Sweta Shah / Vishal Kamat / Ishita Chatterjee / Jon Popke / Adelekan Oyejide / Wei Keat Lim / Jee H Kim / Tammy Huang / Matthew Franklin / William Olson / Thomas Norton / Lorah Perlee / George D Yancopoulos / Andrew J Murphy / Matthew A Sleeman / Jamie M Orengo /
Abstract: The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies ...The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.
History
DepositionOct 5, 2022-
Header (metadata) releaseJan 25, 2023-
Map releaseJan 25, 2023-
UpdateJan 25, 2023-
Current statusJan 25, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28523.png

Downloads & links

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Map

FileDownload / File: emd_28523.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 0.104
Minimum - Maximum-0.15274912 - 0.5845377
Average (Standard dev.)-0.00026405262 (±0.012225482)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 258.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_28523_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_28523_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of IL2Rgamma extracellular domain with Fab fragments of a...

EntireName: Complex of IL2Rgamma extracellular domain with Fab fragments of antibodies REGN7257 and REGN9432
Components
  • Complex: Complex of IL2Rgamma extracellular domain with Fab fragments of antibodies REGN7257 and REGN9432
    • Protein or peptide: Cytokine receptor common subunit gamma
    • Protein or peptide: REGN7257 Fab heavy chain
    • Protein or peptide: REGN7257 Fab light chain
    • Protein or peptide: REGN9432 Fab heavy chain
    • Protein or peptide: REGN9432 Fab light chain

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Supramolecule #1: Complex of IL2Rgamma extracellular domain with Fab fragments of a...

SupramoleculeName: Complex of IL2Rgamma extracellular domain with Fab fragments of antibodies REGN7257 and REGN9432
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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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: 31.617098 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 EQKLISE EDLGGEQKLI SEEDLHHHHH H

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Macromolecule #2: REGN7257 Fab heavy chain

MacromoleculeName: REGN7257 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.607463 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFIFS SYEMHWVRQA PGKGLEWISY ISSSGTTIYY ADSVKGRFTI SRDNAKNSLY LHMNSLRAE DTAVYYCTRA RITGTFDVFD IWGQGTMVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT V SWNSGALT ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFIFS SYEMHWVRQA PGKGLEWISY ISSSGTTIYY ADSVKGRFTI SRDNAKNSLY LHMNSLRAE DTAVYYCTRA RITGTFDVFD IWGQGTMVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VE

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Macromolecule #3: REGN7257 Fab light chain

MacromoleculeName: REGN7257 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.541125 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIFA ASNLQSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QNYNIPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIFA ASNLQSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QNYNIPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #4: REGN9432 Fab heavy chain

MacromoleculeName: REGN9432 Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.323006 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG VVRPGGSLRL SCAASGFTFD DFDMSWVRQG PGKGLEWVSG INWHGSSTGY ADSVKGRFTI SRDNAKNSLY LQMSSLRAE DTALYHCVRG GTIVGATTPL DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EVQLVESGGG VVRPGGSLRL SCAASGFTFD DFDMSWVRQG PGKGLEWVSG INWHGSSTGY ADSVKGRFTI SRDNAKNSLY LQMSSLRAE DTALYHCVRG GTIVGATTPL DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTKTYTCNVD HKPSNTKVDK RVE

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Macromolecule #5: REGN9432 Fab light chain

MacromoleculeName: REGN9432 Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.247803 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT MTCRASRTIS SYLSWYQQKS GKVPNLLIFG ASSLQSGVPS RFSASGSGTD FTLIISSLQP EDFATYYCQ QSYSSPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT MTCRASRTIS SYLSWYQQKS GKVPNLLIFG ASSLQSGVPS RFSASGSGTD FTLIISSLQP EDFATYYCQ QSYSSPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: Ab initio model generation in CryoSparc
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 435563
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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