Martin J. Romeo, PhD, Rachana Agrawal, PhD, Anna Pomés, PhD, Judith A

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Presentation transcript:

A molecular perspective on TH2-promoting cytokine receptors in patients with allergic disease Martin J. Romeo, PhD, Rachana Agrawal, PhD, Anna Pomés, PhD, Judith A. Woodfolk, MBChB, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 4, Pages 952-960.e1 (April 2014) DOI: 10.1016/j.jaci.2013.08.006 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Receptor configurations for TSLP, IL-4, and IL-13. Asterisks indicate subunits shared among different receptor complexes. Green and gold arrows denote putative interactions between IL-4Rα and IL-13Rα2 to form a signaling-inert complex. Functional outcomes are listed for human subjects (1) and mice (2). DC, Dendritic cell. Journal of Allergy and Clinical Immunology 2014 133, 952-960.e1DOI: (10.1016/j.jaci.2013.08.006) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Assembly of type I and type II receptor complexes. A, Ribbon diagrams for IL-4 (PDB: 1ITM) and IL-13 (PDB: 1IJZ). B, Assembly of the IL-4 type I receptor and the IL-13 type II receptor (upper and lower panels, respectively). Upper panel, Blue and green regions denote membrane-distal and membrane-proximal FNIII domains, respectively, of IL-4Rα. The circle denotes site I. Lower panel, Immunoglobulin-like domain (blue) and membrane-distal and membrane-proximal FNIII domains (green and mixed, respectively) are shown for IL-13Rα1. The circle denotes site IIa. Stepwise assembly of receptor-ligand complexes is based on the x-ray crystal structures of fully assembled complexes obtained from www.rcsb.org/pdb (IL-4/IL-4Rα/γc: PDB, 3BPL; type II receptor complex: PDB, 3BPO). Reprinted with permission from La Porte et al.4 Journal of Allergy and Clinical Immunology 2014 133, 952-960.e1DOI: (10.1016/j.jaci.2013.08.006) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Treatments targeting TH2-promoting pathways. Drugs are categorized according to how they act in steps of the receptor assembly process. *Molecules in the research phase. Journal of Allergy and Clinical Immunology 2014 133, 952-960.e1DOI: (10.1016/j.jaci.2013.08.006) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Sequence similarity among the structurally conserved regions of TSLP, IL-4, and IL-13. Sequence alignments for TSLP, IL-4, and IL-13 and related IL-2 subfamily members (IL-2 and IL-7) within the α-helices A, C, and D. α-Helices were determined from x-ray structural data for IL-4 (PDB: 1ITM) and IL-13 (PDB: 1IJZ) and from prediction of the secondary structure for TSLP (JPred prediction algorithm). Coloring denotes sequence identity or similarity. Black highlighting denotes conserved hydrophobic core residues. Underlining denotes a region containing 3 basic residues (KKR) corresponding to a “hot spot” for IL-13 binding to IL-13Rα1 and IL-13Rα2. TSLP contains 3 basic residues at this site (RRR). Journal of Allergy and Clinical Immunology 2014 133, 952-960.e1DOI: (10.1016/j.jaci.2013.08.006) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions