PhD defence R. (Ruixue) Xu

Diverse substrate scaffolds by multicomponent reactions and protein structural dynamics by single-molecule FRET

This dissertation of Ruixue Xu is scientifically divided into two main parts; Part I describes the assessment of diverse substrate scaffolds using multicomponent reaction chemistry. The excellent maneuverability and efficiency of multicomponent reactions combined with high-throughput synthesis allow generating big synthesis data. This enables the deeper exploration of the chemical space in a fast, low-cost, and environment-friendly manner. Further coupling with high-throughput screening methods can lead to an acceleration in the early stage of drug discovery. Part Ⅱ demonstrates that bilobed proteins bearing a common primordial structural core diversified into transcription factors, enzymes, and extra-cytoplasmic transport-related proteins. The reason is that evolutionary modifications primarily at its termini enabled distinct structural dynamics. Substrate-binding domain 2, one of those bilobed proteins, undergoes a large conformational change upon ligand binding. The allosteric coupling of substrate-binding domain 2 is specific to L-glutamine, whereas altering structural dynamics can adapt protein for additional ligands. Understanding the molecular determinants of this specificity and/or intramolecular allosteric communication is critical to understanding protein evolution and the development of therapeutics. Drug design benefits not only from generating extensive compounds libraries but also from a better understanding of drug targets, especially very dynamic ones, since the visible pocket from a PDB structure may not exist.

Promotores Prof.dr. A.S.S. Dömling and Prof.dr. T. Economou