Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.658505
Title: Variable domain orientations in antigen receptors
Author: Dunbar, James
ISNI:       0000 0004 5354 2639
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Abstract:
Specific recognition of pathogenic molecules by the immune system is mediated by proteins known as antigen receptors. One such component is the antibody. Binding properties of natural and engineered antibodies can be understood by studying the structure of their variable domains, VH and VL. In this thesis we investigate how the two variable domains orientate with respect to one another and therefore influence the geometry of the antigen binding site which is formed between them. We describe a method which fully characterises the VH-VL orientation in a consistent and absolute sense using five angles and a distance. The ABangle method is used to investigate variable domain orientation in structures collected by our database SAbDab. Using the ABangle method we compare VH-VL orientation to the corresponding property in a different component of the immune system, the T-cell receptor (TCR). Despite having similar individual domain structures the variable domain orientations of antibodies and TCRs are found to be distinct. This is found to affect an antibody’s ability to mimic TCR specificity. ABangle's characterisation is used to find determinants of the VH-VL orientation. We identify sequence and structural properties that influence the variable domain pose. A feature based method for predicting VH-VL orientation is presented and assessed. Future directions of this research and its application to the development of antibody therapeutics are described.
Supervisor: Deane, Charlotte M.; Fuchs, Angelika; Shi, Jiye Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.658505  DOI: Not available
Keywords: Bioinformatics (life sciences) ; Computational biochemistry ; Immunology ; Antibodies ; Structural Biology ; Computational Biology ; Protein Engineering
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