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Open data
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Basic information
Entry | Database: PDB / ID: 5j11 | ||||||
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Title | Structure of human TSLP in complex with TSLPR and IL-7Ralpha | ||||||
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![]() | SIGNALING PROTEIN / cytokine inflammation TSLP signaling complex | ||||||
Function / homology | ![]() positive regulation of chemokine (C-C motif) ligand 1 production / positive regulation of granulocyte colony-stimulating factor production / interleukin-7 receptor activity / interleukin-7 receptor binding / interleukin-7-mediated signaling pathway / positive regulation of mast cell activation / positive regulation of receptor signaling pathway via STAT / negative regulation of T cell mediated cytotoxicity / regulation of DNA recombination / positive regulation of cytokine-mediated signaling pathway ...positive regulation of chemokine (C-C motif) ligand 1 production / positive regulation of granulocyte colony-stimulating factor production / interleukin-7 receptor activity / interleukin-7 receptor binding / interleukin-7-mediated signaling pathway / positive regulation of mast cell activation / positive regulation of receptor signaling pathway via STAT / negative regulation of T cell mediated cytotoxicity / regulation of DNA recombination / positive regulation of cytokine-mediated signaling pathway / positive regulation of T cell differentiation in thymus / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / negative regulation of T cell apoptotic process / cellular homeostasis / cytokine receptor activity / regulation of cell size / B cell proliferation / T cell homeostasis / cytokine binding / cell surface receptor signaling pathway via JAK-STAT / B cell homeostasis / positive regulation of interleukin-10 production / hemopoiesis / defense response to fungus / lymph node development / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-7 signaling / clathrin-coated endocytic vesicle membrane / cytokine activity / antigen binding / positive regulation of receptor signaling pathway via JAK-STAT / cell morphogenesis / T cell mediated cytotoxicity / cytokine-mediated signaling pathway / positive regulation of inflammatory response / positive regulation of interleukin-6 production / Cargo recognition for clathrin-mediated endocytosis / antimicrobial humoral immune response mediated by antimicrobial peptide / Clathrin-mediated endocytosis / gene expression / T cell differentiation in thymus / defense response to Gram-negative bacterium / receptor complex / cell surface receptor signaling pathway / defense response to Gram-positive bacterium / immune response / external side of plasma membrane / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular space / extracellular region / nucleoplasm / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Verstraete, K. / Savvides, S.N. | ||||||
![]() | ![]() Title: Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Authors: Kenneth Verstraete / Frank Peelman / Harald Braun / Juan Lopez / Dries Van Rompaey / Ann Dansercoer / Isabel Vandenberghe / Kris Pauwels / Jan Tavernier / Bart N Lambrecht / Hamida Hammad / ...Authors: Kenneth Verstraete / Frank Peelman / Harald Braun / Juan Lopez / Dries Van Rompaey / Ann Dansercoer / Isabel Vandenberghe / Kris Pauwels / Jan Tavernier / Bart N Lambrecht / Hamida Hammad / Hans De Winter / Rudi Beyaert / Guy Lippens / Savvas N Savvides / ![]() ![]() ![]() Abstract: The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma ...The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 398.8 KB | Display | ![]() |
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PDB format | ![]() | 331.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 479.8 KB | Display | ![]() |
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Full document | ![]() | 483.3 KB | Display | |
Data in XML | ![]() | 19.3 KB | Display | |
Data in CIF | ![]() | 26.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 5j13C ![]() 3di2S S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
-Protein , 3 types, 3 molecules ABC
#1: Protein | Mass: 16523.906 Da / Num. of mol.: 1 Mutation: Residues 127 to 131 were deleted in the construct used for crystallisation. Source method: isolated from a genetically manipulated source Details: Before crystallisation, the N-terminal His-tag (residues 1 - 17, MGSSHHHHHHSSGLVPR) was removed by thrombin cleavage. Residues 127 to 131 of TSLP (127-RRKRK-131) (according to the reference ...Details: Before crystallisation, the N-terminal His-tag (residues 1 - 17, MGSSHHHHHHSSGLVPR) was removed by thrombin cleavage. Residues 127 to 131 of TSLP (127-RRKRK-131) (according to the reference sequence numbering scheme for TSLP) were deleted in the construct used for crystallization. Source: (gene. exp.) ![]() Details (production host): ORF cloned between NdeI and BamHI sites Production host: ![]() ![]() |
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#2: Protein | Mass: 27592.170 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Before crystallisation, the N-terminal His-tag (residues 1 - 17, MGSSHHHHHHSSGLVPR) was removed by thrombin cleavage. Source: (gene. exp.) ![]() Details (production host): ORF cloned between NdeI and BamHI sites Production host: ![]() ![]() |
#3: Protein | Mass: 26573.562 Da / Num. of mol.: 1 / Mutation: N47Q Source method: isolated from a genetically manipulated source Details: The signal peptide (residues 1 - 24) is removed from the mature protein. Source: (gene. exp.) ![]() Details (production host): stable cell line, tetracycline inducible expression Cell line (production host): HEK293S MGAT1-/- / Production host: ![]() |
-Sugars , 1 types, 2 molecules ![](data/chem/img/NAG.gif)
#5: Sugar |
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-Non-polymers , 2 types, 30 molecules ![](data/chem/img/PGE.gif)
![](data/chem/img/HOH.gif)
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#4: Chemical | ChemComp-PGE / |
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#6: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.05 Å3/Da / Density % sol: 59.72 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.8 Details: 0.02 M Citric acid 0.08 M BIS-TRIS propane 16% w/v polyethylene glycol 3350 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 30, 2015 |
Radiation | Monochromator: Si[111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9801 Å / Relative weight: 1 |
Reflection | Resolution: 2.56→50 Å / Num. obs: 24638 / % possible obs: 97.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 69.9 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.062 / Net I/σ(I): 14.2 |
Reflection shell | Resolution: 2.56→2.72 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.7 / Rrim(I) all: 0.776 / % possible all: 94.2 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: X-ray structure of human TSLP in complex with human TSLPR and mouse IL-7Ralpha; PDB 3DI2: chain B Resolution: 2.56→45.76 Å / Cor.coef. Fo:Fc: 0.9349 / Cor.coef. Fo:Fc free: 0.9285 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.319 / SU Rfree Blow DPI: 0.219
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Displacement parameters | Biso mean: 88.73 Å2
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Refine analyze | Luzzati coordinate error obs: 0.328 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.56→45.76 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.56→2.67 Å / Total num. of bins used: 12
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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