Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789118
Title: Investigating allostery in IgE-Fc using a panel of anti-IgE antibodies
Author: Allan, Elizabeth
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
The interactions between immunoglobulin E (IgE) and its receptors, FcɛRI and CD23, regulate a number of important processes in allergic disorders. The Fc fragment of IgE, which binds the receptors, has a high degree of conformational plasticity and can be allosterically modulated. A comprehensive understanding of IgE-Fc dynamics and allosteric modulation could provide insights that enable the development of novel therapeutics for asthma and allergy. Using UCB's Core Antibody Discovery Process we screened the immune repertoire of rabbits immunized against IgE-Fc for antibodies that bind IgE-Fc and affect the IgE-Fc/CD23 interaction. Surface plasmon resonance (SPR) was used to identify a subset of antibodies that elicit their effect on IgE-Fc-receptor binding allosterically. Kinetic and thermodynamic interaction studies of these antibodies are helping to elucidate the mechanisms of allostery in IgE-Fc. Allosteric communication in IgE-Fc has previously only been demonstrated between two sites within the same domain; here we show for the first time that allostery in IgE-Fc can occur across different domains over long distances. We suggest that allostery in IgE-Fc is not binary in character; certain domain orientations cannot always be attributed to inhibition of receptor binding. Rather, we advocate an ensemble treatment of allostery, in which allosteric phenomena are due to the intrinsic dynamic properties of the IgE-Fc protein. X-ray crystallographic structures of transiently populated conformations of IgE-Fc trapped by anti-IgE antibodies will provide insights into the energy landscape of IgE-Fc and the importance of IgE-Fc dynamics in receptor engagement.
Supervisor: McDonnell, James Michael ; Sutton, Brian John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789118  DOI: Not available
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