The role of docking domains in natural product biosynthesis

"Natural products biosynthesised by multimodular mega synthetase assembly lines such as polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) in bacteria have many pharmaceutical and agricultural applications. Interactions between modules in these assembly lines are often mediated by C-terminal glutamine-rich short linear motifs (SliMs) and N-terminal b-hairpin docking (betaHD) domain interactions. This includes anticancer and herbicidal bicyclic nonribosomal depsipeptide histone deacetylase inhibitors (HDACis), and anticoagulant serine protease inhibitors, aeruginosins.
Utilisation of these SliM:betaHD domain mediated interactions is a promising tool in the engineering of biosynthetic pathways to produce new natural product analogues with improved bioactivity activity. This project aims to fully characterise these SliM:betaHD domain mediated interactions in aeruginosin and HDACi pathways via; in vitro reconstitution of the pathways; using biophysical techniques such as X-ray crystallography and NMR spectroscopy to investigate the structural basis of specificity; testing our hypotheses through creation of point mutations and enzyme chimeras; exploring enzymatic crosstalk in vitro to create novel analogues; and in vivo engineering to create artificial de novo biosynthesis pathways."