7mxi

IgE-Fc in complex with DARPins E2_79 and E3_53

spinqualitylabelsall models 7mxi, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7mxi is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: BMA, FUC, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IGHE_HUMAN Publication Abstract from PubMed BACKGROUND: Anaphylaxis represents one of the most severe and fatal forms of allergic reactions. Like most other allergies, it is caused by activation of basophils and mast cells by allergen-mediated cross-linking of IgE bound to its high-affinity receptor, FcepsilonRI, on the cell surface. The systemic release of soluble mediators induces an inflammatory cascade, rapidly causing symptoms with peak severity in minutes to hours after allergen exposure. Primary treatment for anaphylaxis consists of immediate intramuscular administration of adrenaline. OBJECTIVE: While adrenaline alleviates life-threatening symptoms of an anaphylactic reaction, there are currently no disease-modifying interventions available. We sought to develop potent and fast-acting IgE inhibitors with the potential to rapidly terminate acute allergic reactions. METHODS: Using affinity maturation by yeast display and structure-guided molecular engineering, we generated 3 optimized disruptive IgE inhibitors based on designed ankyrin repeat proteins and assessed their ability to actively remove IgE from allergic effector cells in vitro as well as in vivo in mice. RESULTS: The engineered IgE inhibitors rapidly dissociate preformed IgE:FcepsilonRI complexes, terminate IgE-mediated signaling in preactivated human blood basophils in vitro, and shut down preinitiated allergic reactions and anaphylaxis in mice in vivo. CONCLUSIONS: Fast-acting disruptive IgE inhibitors demonstrate the feasibility of developing kinetically optimized inhibitors for the treatment of anaphylaxis and the rapid desensitization of allergic individuals. Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions.,Pennington LF, Gasser P, Brigger D, Guntern P, Eggel A, Jardetzky TS J Allergy Clin Immunol. 2021 Oct;148(4):1049-1060. doi: , 10.1016/j.jaci.2021.03.050. Epub 2021 May 12. PMID:33991582 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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