5j13
From Proteopedia
Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157)
Structural highlights
FunctionTSLP_HUMAN Isoform 1: Cytokine that induces the release of T-cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells. Can induce allergic inflammation by directly activating mast cells.[1] [2] [3] Isoform 2: May act as an antimicrobial peptide in the oral cavity and on the skin.[4] Publication Abstract from PubMedThe 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. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.,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 Nat Commun. 2017 Apr 3;8:14937. doi: 10.1038/ncomms14937. PMID:28368013[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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