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Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937.

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.

Author information

1
VIB-UGent Center for Inflammation Research, Zwijnaarde, Ghent 9052, Belgium.
2
Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ghent 9000, Belgium.
3
VIB-UGent Center for Medical Biotechnology, Ghent 9000, Belgium.
4
Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde, Ghent 9052, Belgium.
5
Unité de Glycobiologie Structurale et Fonctionnelle-CNRS UMR8576, Université de Lille, Villeneuve d'Ascq 59655, France.
6
Sciences Department-Chemistry, Pontifical Catholic University of Peru, Lima 32, Peru.
7
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk 2610, Belgium.
8
VIB-VUB Center for Structural Biology, Brussels 1050, Belgium.
9
Structural Biology Brussels, Bio-Engineering Sciences Department, Vrije Universiteit Brussel, Brussels 1050, Belgium.
10
Department of Respiratory Medicine, Ghent University Hospital, Ghent 9000, Belgium.
11
LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse 31400, France.

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.

PMID:
28368013
PMCID:
PMC5382266
DOI:
10.1038/ncomms14937
[Indexed for MEDLINE]
Free PMC Article

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