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- PDB-7uwl: Structure of the IL-25-IL-17RB-IL-17RA ternary complex -

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Basic information

Entry
Database: PDB / ID: 7uwl
TitleStructure of the IL-25-IL-17RB-IL-17RA ternary complex
Components
  • Interleukin-17 receptor A
  • Interleukin-17 receptor B
  • Interleukin-25
KeywordsCYTOKINE / Receptor complex / IL-17E / IL-25 / IL-17RB / IL-17RA
Function / homology
Function and homology information


interleukin-17E receptor binding / interleukin-17 receptor activity / eosinophil differentiation / granulocyte chemotaxis / Interleukin-17 signaling / T-helper 17 type immune response / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / positive regulation of chemokine (C-X-C motif) ligand 1 production / response to nematode ...interleukin-17E receptor binding / interleukin-17 receptor activity / eosinophil differentiation / granulocyte chemotaxis / Interleukin-17 signaling / T-helper 17 type immune response / interleukin-17A-mediated signaling pathway / positive regulation of interleukin-23 production / positive regulation of chemokine (C-X-C motif) ligand 1 production / response to nematode / response to fungus / interleukin-17-mediated signaling pathway / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / fibroblast activation / positive regulation of cytokine production involved in inflammatory response / inflammatory response to antigenic stimulus / cytokine receptor activity / defense response to fungus / cytokine activity / regulation of cell growth / response to virus / protein catabolic process / defense response / positive regulation of inflammatory response / positive regulation of interleukin-6 production / cell surface receptor signaling pathway / inflammatory response / intracellular membrane-bounded organelle / innate immune response / signaling receptor binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / membrane / plasma membrane
Similarity search - Function
Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor A/B, FnIII-like domain 1 superfamily / Interleukin-17 receptor A/B, FnIII-like domain 2 superfamily / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin 17 receptor D / Interleukin-17 receptor-like / SEFIR domain / SEFIR domain / SEFIR domain profile. / Interleukin-17 family ...Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin-17 receptor A/B, FnIII-like domain 1 superfamily / Interleukin-17 receptor A/B, FnIII-like domain 2 superfamily / Interleukin-17 receptor, fibronectin-III-like domain 1 / Interleukin 17 receptor D / Interleukin-17 receptor-like / SEFIR domain / SEFIR domain / SEFIR domain profile. / Interleukin-17 family / Interleukin-17 / Cystine-knot cytokine
Similarity search - Domain/homology
Interleukin-17 receptor A / Interleukin-25 / Interleukin-17 receptor B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsWilson, S.C. / Caveney, N.A. / Jude, K.M. / Garcia, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI51321 United States
CitationJournal: Nature / Year: 2022
Title: Organizing structural principles of the IL-17 ligand-receptor axis.
Authors: Steven C Wilson / Nathanael A Caveney / Michelle Yen / Christoph Pollmann / Xinyu Xiang / Kevin M Jude / Maximillian Hafer / Naotaka Tsutsumi / Jacob Piehler / K Christopher Garcia /
Abstract: The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ...The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases. The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses. Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25-IL-17RB homodimer is flanked by two 'wing-like' IL-17RA co-receptors through a 'tip-to-tip' geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB-IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A-IL-17RA and IL-17A-IL-17RA-IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.
History
DepositionMay 3, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Sep 7, 2022Group: Database references / Category: citation / Item: _citation.title
Revision 1.3Sep 28, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-25
B: Interleukin-25
C: Interleukin-17 receptor B
D: Interleukin-17 receptor B
E: Interleukin-17 receptor A
F: Interleukin-17 receptor A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)188,85024
Polymers184,0566
Non-polymers4,79518
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Interleukin-25 / IL-25 / Interleukin-17E / IL-17E


Mass: 21490.201 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL25, IL17E, UNQ3120/PRO10272 / Production host: Homo sapiens (human) / References: UniProt: Q9H293
#2: Protein Interleukin-17 receptor B / IL-17 receptor B / IL-17RB / Cytokine receptor-like 4 / IL-17 receptor homolog 1 / IL-17Rh1 / ...IL-17 receptor B / IL-17RB / Cytokine receptor-like 4 / IL-17 receptor homolog 1 / IL-17Rh1 / IL17Rh1 / Interleukin-17B receptor / IL-17B receptor


Mass: 33649.098 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL17RB, CRL4, EVI27, IL17BR, UNQ2501/PRO19612 / Production host: Homo sapiens (human) / References: UniProt: Q9NRM6
#3: Protein Interleukin-17 receptor A / IL-17 receptor A / IL-17RA / CDw217


Mass: 36888.617 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL17RA, IL17R / Production host: Homo sapiens (human) / References: UniProt: Q96F46
#4: 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.: 4
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
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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: ternary IL-25-IL-17RB-IL-17RA complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 53 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1287497 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01410360
ELECTRON MICROSCOPYf_angle_d1.2914097
ELECTRON MICROSCOPYf_dihedral_angle_d7.7781469
ELECTRON MICROSCOPYf_chiral_restr0.051631
ELECTRON MICROSCOPYf_plane_restr0.0061802

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