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- PDB-8epa: Structure of interleukin receptor common gamma chain (IL2Rgamma) ... -

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Basic information

Entry
Database: PDB / ID: 8epa
TitleStructure of interleukin receptor common gamma chain (IL2Rgamma) in complex with two antibodies
Components
  • (REGN7257 Fab ...) x 2
  • (REGN9432 Fab ...) x 2
  • Cytokine receptor common subunit gamma
KeywordsIMMUNE SYSTEM / interleukin signaling / lymphocyte maturation / blocking antibody / immunoglobulin
Function / homology
Function and homology information


interleukin-7-mediated signaling pathway / mature B cell differentiation / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / interleukin-15 receptor activity / interleukin-2 binding / 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 / CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / interleukin-15 receptor activity / interleukin-2 binding / 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 / STAT3 nuclear events downstream of ALK signaling / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / cytokine receptor activity / Interleukin-2 signaling / 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 / T cell differentiation in thymus / gene expression / 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 speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsFranklin, M.C. / Romero Hernandez, A.
Funding support1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
I: Cytokine receptor common subunit gamma
H: REGN7257 Fab heavy chain
L: REGN7257 Fab light chain
A: REGN9432 Fab heavy chain
B: REGN9432 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,7616
Polymers125,3365
Non-polymers4241
Water0
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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Antibody , 4 types, 4 molecules HLAB

#2: Antibody REGN7257 Fab heavy chain


Mass: 23607.463 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody REGN7257 Fab light chain


Mass: 23541.125 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody REGN9432 Fab heavy chain


Mass: 23323.006 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#5: Antibody REGN9432 Fab light chain


Mass: 23247.803 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)

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Protein / Sugars , 2 types, 2 molecules I

#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: 31617.098 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
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Details

Has ligand of interestN

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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: Complex of IL2Rgamma extracellular domain with Fab fragments of antibodies REGN7257 and REGN9432
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM softwareName: EPU / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 435563 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 114.63 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00375173
ELECTRON MICROSCOPYf_angle_d0.67317018
ELECTRON MICROSCOPYf_chiral_restr0.0457757
ELECTRON MICROSCOPYf_plane_restr0.0049896
ELECTRON MICROSCOPYf_dihedral_angle_d7.485705

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