Structural biology in action: investigating EGFR mutations in lung cancer and engineering biosynthetic enzymes

The theme of the thesis is to demonstrate the power of structural biology, through both computational and experimental approaches, in understanding protein function and guiding practical applications in two distinct areas: precision oncology and enzyme engineering.The first part involves computational modelling to investigate the structural and functional impact of EGFR mutations in NSCLC and their implications for tyrosine kinase inhibitor treatment. Chapters 2 focus on computational modelling of novel EGFR mutations to assess their impact on kinase activation and tyrosine kinase inhibitor efficacy. Chapter 3 includes a prediction analysis of modelling on the treatment outcomes for NSCLC patients harbouring EGFR exon 20 insertions. Chapters 4 specifically discussed the clinical insights and outcomes from a periodic review of patients with rare EGFR mutations who received MTB-advised targeted therapies, with a subgroup of patients receiving therapy guided by computational modelling had a higher response rate. The second part focuses on structural biology techniques, particularly X-ray crystallography, to support the characterisation of biosynthetic enzymes. Chapters 5 & 6 involve the rational engineering of a plant polyketide synthase for the biosynthesis of methylated flavonoids and a substrate scope study of bacterial O-methyltransferases. Both studies are supported by x-ray crystal structures, captured in both apo form and with bound product or cofactor.

Dissertation: https://hdl.handle.net/11370/751ddb4e-5122-4e07-adee-517421446440