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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Thermal sensitivity and flexibility of the Cε3 domains in immunoglobulin E Katy A. Dore , Anna M. Davies , Nyssa Drinkwater , Andrew J. Beavil , James M. Mcdonnell , Brian J. Sutton Biochimica Et Biophysica Acta (bba) - Proteins And Proteomics DOI: 10.1016/j.bbapap.2017.08.005 Diamond Proposal Number(s): [1220, 9495] Open Access Show Abstract ▼ Abstract: Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcεRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cε2, Cε3 and Cε4 domains. A sub-fragment lacking the Cε2 domains, Fcε3–4, also binds to both receptors, although receptor binding almost exclusively involves the Cε3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcε3–4 at the highest resolutions yet determined, 1.75 Å and 2.0 Å respectively, revealing unprecedented detail regarding the carbohydrate and its interactions with protein domains. Analysis of the crystallographic B factors of these, together with all earlier IgE-Fc and Fcε3–4 structures, shows that the Cε3 domains exhibit the greatest intrinsic flexibility and quaternary structural variation within IgE-Fc. Intriguingly, both well-ordered carbohydrate and disordered polypeptide can be seen within the same Cε3 domains. A simplified method for comparing the quaternary structures of the Cε3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcεRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcε3–4 identifies Cε3 as the domain most susceptible to thermally-induced unfolding, and responsible for the characteristically low melting temperature of IgE.	Aug 2017
I03-Macromolecular Crystallography	Human immunoglobulin E flexes between acutely bent and extended conformations Nyssa Drinkwater , Benjamin P. Cossins , Anthony H. Keeble , Michael Wright , Katharine Cain , Hanna Hailu , Amanda Oxbrow , Jean Delgado , Lindsay K Shuttleworth , Michael W.-P. Kao , James M. Mcdonnell , Andrew J. Beavil , Alistair J. Henry , Brian J. Sutton Nature Structural & Molecular Biology 21 (4), 397 - 404 DOI: 10.1038/nsmb.2795 PMID: 24632569 Show Abstract ▼ Abstract: Crystallographic and solution studies have shown that IgE molecules are acutely bent in their Fc region. Crystal structures reveal the Cɛ2 domain pair folded back onto the Cɛ3-Cɛ4 domains, but is the molecule exclusively bent or can the Cɛ2 domains adopt extended conformations and even 'flip' from one side of the molecule to the other? We report the crystal structure of IgE-Fc captured in a fully extended, symmetrical conformation and show by molecular dynamics, calorimetry, stopped-flow kinetic, surface plasmon resonance (SPR) and Förster resonance energy transfer (FRET) analyses that the antibody can indeed adopt such extended conformations in solution. This diversity of conformational states available to IgE-Fc offers a new perspective on IgE function in allergen recognition, as part of the B-cell receptor and as a therapeutic target in allergic disease.	Mar 2014

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