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- PDB-5j13: Structural basis for TSLP antagonism by the therapeutic antibody ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 5j13 | ||||||
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Title | Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157) | ||||||
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![]() | IMMUNE SYSTEM / cytokine inflammation TSLP antibody | ||||||
Function / homology | ![]() positive regulation of chemokine (C-C motif) ligand 1 production / positive regulation of granulocyte colony-stimulating factor production / interleukin-7 receptor binding / positive regulation of mast cell activation / positive regulation of receptor signaling pathway via STAT / positive regulation of cytokine-mediated signaling pathway / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / positive regulation of interleukin-10 production / defense response to fungus ...positive regulation of chemokine (C-C motif) ligand 1 production / positive regulation of granulocyte colony-stimulating factor production / interleukin-7 receptor binding / positive regulation of mast cell activation / positive regulation of receptor signaling pathway via STAT / positive regulation of cytokine-mediated signaling pathway / positive regulation of interleukin-13 production / positive regulation of interleukin-5 production / positive regulation of interleukin-10 production / defense response to fungus / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-7 signaling / cytokine activity / positive regulation of inflammatory response / antimicrobial humoral immune response mediated by antimicrobial peptide / positive regulation of interleukin-6 production / defense response to Gram-negative bacterium / positive regulation of cell population proliferation / negative regulation of apoptotic process / extracellular space / extracellular region 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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PDBx/mmCIF format | ![]() | 201.9 KB | Display | ![]() |
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PDB format | ![]() | 160 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 447.5 KB | Display | ![]() |
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Full document | ![]() | 447.5 KB | Display | |
Data in XML | ![]() | 20.1 KB | Display | |
Data in CIF | ![]() | 28 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 5j11C ![]() 4hieS ![]() 4hk0S 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 on special symmetry positions |
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Components
#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: Antibody | Mass: 25870.895 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: The signal peptide (residues 1 - 28) is removed from the mature protein. Source: (gene. exp.) ![]() Details (production host): ORF cloned between AgeI and KpnI sites Cell line (production host): HEK-293T / Production host: ![]() | ||
#3: Antibody | Mass: 28438.221 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: The signal peptide (residues 1 - 28) is removed from the mature protein. Source: (gene. exp.) ![]() Details (production host): ORF cloned between AgeI and KpnI sites Cell line (production host): HEK-293T / Production host: ![]() | ||
#4: Chemical | #5: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.26 Å3/Da / Density % sol: 45.49 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.6 Details: 0.2 M ammonium sulfate 0.1 M sodium acetate pH 4.6 25% w/v polyethylene glycol 4000 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 17, 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: 2.298→55 Å / Num. obs: 25284 / % possible obs: 97 % / Redundancy: 8.4 % / Biso Wilson estimate: 47.33 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.11 / Net I/σ(I): 14.23 |
Reflection shell | Resolution: 2.298→2.44 Å / Redundancy: 4.2 % / Mean I/σ(I) obs: 1.6 / Rrim(I) all: 0.747 / % possible all: 83.8 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 4HK0, chain B; 4HIE, chain B Resolution: 2.298→44.796 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 23.26 Details: - rigid body refinement (single rigid body per domain) - Iterative cycles of refinement, model (re)building and validation xyz coordinate refinement real-space refinement individual B- ...Details: - rigid body refinement (single rigid body per domain) - Iterative cycles of refinement, model (re)building and validation xyz coordinate refinement real-space refinement individual B-factors riding hydrogens optimisation of X-ray/stereochemistry weight optimisation of X-ray/ADP weight structure validation in COOT, Phenix (Molprobity) and PDB_REDO
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.298→44.796 Å
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Refine LS restraints |
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LS refinement shell |
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