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

Article Details

Citation

Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, Vandenberghe I, Pauwels K, Tavernier J, Lambrecht BN, Hammad H, De Winter H, Beyaert R, Lippens G, Savvides SN

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

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

PubMed ID
28368013 [ View in PubMed
]
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 alpha-chain (IL-7Ralpha) 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-7Ralpha extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
TezepelumabThymic stromal lymphopoietinProteinHumans
Yes
Binder
Antibody
Details