Elucidating the Conformational and Binding Properties of Compact Disordered Proteins

Abstract

Compact disordered regions are a subtype of intrinsic disorder within proteins characterised by fluctuating secondary structures. The dynamic nature of such proteins are challenging to analyse using traditional methods due to their sensitivity outside of their native conditions, causing a bias towards certain conformations. CDRs are abundant in proteins associated with a range of health disorders making them promising therapeutic targets, however, a lack of understanding of CDR behaviours makes novel structure based ligand design and understanding binding mechanisms difficult. The project has been focused on the NMR analysis of transcription factor - cMyc, which contains a basic helix-loop-helix leucine zipper (bHLH-LZ) domain (10500 kDa) of which when unbound has compact disordered structure which becomes more ordered upon binding to Max. To understand the range of structural conformations and the mechanisms of protein folding, several methods have been utilised to increase the longevity of certain intermittent structures within the domain including physical and chemical denaturing conditions, amino acid substitution, ligand binding, and macrocyclisation. Molecular modelling was utilised to predict conformations which cannot be elucidated through experimental techniques. To validate the precision and accuracy of the NMR and MD findings g-factor spectroscopy will be used to provide additional structural data.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Almond (Supervisor), Jonathan Waltho (Supervisor) & Matthew Cliff (Supervisor)