5J11

Structure of human TSLP in complex with TSLPR and IL-7Ralpha

Summary for 5J11

• Entry DOI: 10.2210/pdb5j11/pdb
• Descriptor: Thymic stromal lymphopoietin, Interleukin-7 receptor subunit alpha, Cytokine receptor-like factor 2, ... (6 entities in total)
• Functional Keywords: cytokine inflammation tslp signaling complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 71282.23

Authors

Verstraete, K.,Savvides, S.N. (deposition date: 2016-03-28, release date: 2017-04-05, Last modification date: 2024-11-20)

Primary citation

Verstraete, K.,Peelman, F.,Braun, H.,Lopez, J.,Van Rompaey, D.,Dansercoer, A.,Vandenberghe, I.,Pauwels, K.,Tavernier, J.,Lambrecht, B.N.,Hammad, H.,De Winter, H.,Beyaert, R.,Lippens, G.,Savvides, S.N.
Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.
Nat Commun, 8:14937-14937, 2017

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 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.

PubMed: 28368013
DOI: 10.1038/ncomms14937

Experimental method

X-RAY DIFFRACTION (2.56 Å)