5j13

From Proteopedia

Structural basis for TSLP antagonism by the therapeutic antibody Tezepelumab (MEDI9929 / AMG-157)

PDB ID 5j13

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Structural highlights

5j13 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.298Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TSLP_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 PubMed

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.

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

↑ Reche PA, Soumelis V, Gorman DM, Clifford T, Liu Mr, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal Malefyt R, Kastelein RA, Bazan JF. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J Immunol. 2001 Jul 1;167(1):336-43. PMID:11418668
↑ Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia. 2001 Aug;15(8):1286-92. PMID:11480573
↑ Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007 Feb 19;204(2):253-8. Epub 2007 Jan 22. PMID:17242164 doi:http://dx.doi.org/jem.20062211
↑ Bjerkan L, Schreurs O, Engen SA, Jahnsen FL, Baekkevold ES, Blix IJ, Schenck K. The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol. 2015 Jan;8(1):49-56. doi: 10.1038/mi.2014.41. Epub 2014 May 21. PMID:24850429 doi:http://dx.doi.org/10.1038/mi.2014.41
↑ 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. PMID:28368013 doi:http://dx.doi.org/10.1038/ncomms14937