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Title: Designing inhibitors of activator protein 1 based on the leucine zipper motif
Author: Crooks , R. O.
Awarding Body: University of Essex
Current Institution: University of Essex
Date of Award: 2013
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The transcription factor Activator Protein 1 (AP-1) is a dimeric DNA binding protein, which plays an important role in the development and progression of numerous cancers, and has consequently attracted interest as a target in cancer therapy. Of particular importance to the function of AP-1 is the leucine zipper (LZ) domain, a 32 residue sequence motif contained within the protein that allows for dimerisation to take place. As this is a requirement for AP-1 to bind to DNA, this is a promising strategy for its inhibition. In recent years, peptides have been of growing interest as pharmaceutical agents, owing to their advantageous properties and these have shown promise in previous research concerning AP-1 inhibition. Using a combination of experimental and computational approaches, this thesis explores strategies used to design inhibitors of AP-1 . It was demonstrated, using a library screen protein fragment complementation assay (peA), coupled with rational library design, that truncation of an inhibitor template could yield a shorter sequence which retains the inhibitory function of the template I sequence. This demonstrates a semi-rational approach to the design of LZ based peptide inhibitors. Using sequence data mining, residue selection preferences were studied for less well understood solvent exposed residues in LZ domains in order to derive selection rules for these residues. Finally, design rules for LZ domains were combined into an algorithm which aims to predict inhibitors towards sequences. The results of these computational studies are not generally successful and so this thesis speculates that there are shortcomings in the rules presently used to design and predict LZ domains de novo. In particular design rules used for rational design need to make sequence context considerations, as opposed to single residue pairing decisions. Once derived however, such rules can be simply incorporated into the design process, giving scope for future enhancement.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available