title: Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.
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 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.
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Verstraete
authors.affiliation: VIB-UGent Center for Medical Biotechnology, Ghent 9000, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde, Ghent 9052, Belgium.
authors.forename: Harald
authors.initials: H
authors.lastname: Braun
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle-CNRS UMR8576, Université de Lille, Villeneuve d'Ascq 59655, France.|Sciences Department-Chemistry, Pontifical Catholic University of Peru, Lima 32, Peru.
authors.forename: Juan
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk 2610, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Van Rompaey
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Dansercoer
authors.affiliation: Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Vandenberghe
authors.affiliation: VIB-VUB Center for Structural Biology, Brussels 1050, Belgium.|Structural Biology Brussels, Bio-Engineering Sciences Department, Vrije Universiteit Brussel, Brussels 1050, Belgium.
authors.forename: Kris
authors.identifier: 0000-0002-7341-0890
authors.initials: K
authors.lastname: Pauwels
authors.affiliation: VIB-UGent Center for Medical Biotechnology, Ghent 9000, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Department of Respiratory Medicine, Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Department of Respiratory Medicine, Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Hamida
authors.initials: H
authors.lastname: Hammad
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk 2610, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: De Winter
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde, Ghent 9052, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle-CNRS UMR8576, Université de Lille, Villeneuve d'Ascq 59655, France.|LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse 31400, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.|Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
authors.forename: Savvas N
authors.initials: SN
authors.lastname: Savvides
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D018925:Chemokines / Q000096:biosynthesis; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003713:Dendritic Cells; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006967:Hypersensitivity / Q000276:immunology* / Q000473:pathology; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism*; D017433:Protein Structure, Secondary; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018925:Chemokines; D016207:Cytokines; D046912:Multiprotein Complexes; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; C415350:interleukin-7 receptor, alpha chain; C000622721:tezepelumab; D000094632:Thymic Stromal Lymphopoietin