Title: Synthetic control of bio-architectures: from protein cages to cyclic peptides

Speaker: Dr Yu Heng Lau

Abstract: 

In this seminar, I will discuss two ongoing projects in our lab that exemplify our approach to research at the interface of chemical biology and synthetic biology.

The first project involves the design of synthetic organelles, built from self-assembling proteins, for hosting custom enzymatic reactions such as carbon fixation. Relatively little is known about the fundamentals of such ‘nanoreactor’ systems, especially the molecular parameters that govern their stability and molecular flux through their pores. I will outline our systematic analysis of 24 designed variants based on the T. maritima encapsulin protein organelle, each featuring pores of different size and charge.¹ We combine cryo-EM, molecular dynamics, and stopped flow kinetics, to uncover the complex interplay of factors that determines the kinetics of such nanoreactor systems.

The second project is an exploration of telomeric protein-protein interactions as potential drug targets for ALT-positive cancers. ALT refers to ‘Alternative Lengthening of Telomeres’, a recombination-based mechanism independent of telomerase that 10-15% of all cancers rely on to maintain telomere length and replicate indefinitely. We are using a multi-pronged approach (display screening, rational design, fragments) to develop chemical inhibitors against the FANCM-BTR target,^2,3 an interaction that mediates replication stress and is a vulnerability in ALT-positive cancers.  

1. L. Adamson et al., bioRxiv 2021. doi:10.1101/2021.01.27.428512
2. R. Lu et al., Nat. Commun 2019, 10, 2252.
3. Q. N. Vu et al., RSC Med. Chem. 2021, 12, 887-901.