E3 ubiquitin ligases, of which >600 are predicted to function in humans, catalyse the transfer of ubiquitin to target proteins and confer substrate specificity to ubiquitination. The Ciulli Lab is particularly interested in the human Cullin RING ligases (CRLs), the largest superfamily of E3s (1). CRLs play crucial roles in cellular homeostasis and are implicated in a wide range of diseases, including cancer. Native CRLs assemble in vivo as multiprotein complexes and their ligase activity often requires posttranslational modifications (2). These features render traditional drug discovery approaches unsuitable to effectively block CRL activity with small molecules. Moreover, CRLs are not just target to inhibitors. Small-molecules can also hijack and re-direct CRL catalytic activity toward neo-substrates, triggering their proteasomal degradation (3). Small-molecule mediated protein degradation is emerging as a powerful new modality of chemical biology intervention, and an attractive therapeutic strategy (4).
The proposed project aims to manipulate E3 ligase activity using small molecules targeting CRL surfaces and protein-protein interfaces (PPIs). This multi-disciplinary project will provide the student training in small molecule drug design; fragment-based screening and structure-based design; peptide synthesis; molecular biology and protein biochemistry and crystallography; as well as many other technologies and methods routinely employed in early-stage drug discovery projects. The project will build on our Laboratory expertise on targeting protein surfaces and protein-protein interactions within E3 CRLs using drug-like small molecules, both in their own right as potential inhibitors, as well as ligands for targeted protein degradation by small molecules.
This project will be suitable for an enthusiastic and motivated student with interests in chemical structural biology and medicinal chemistry and ability to actively participate in collaborative multidisciplinary research.
- Bulatov & Ciulli, Biochem J (2015) 467, p.365.
- Petroski et al. Nat Rev Mol Cell Biol (2005) 6, p.9.
- Lucas & Ciulli Curr. Opin. Struct. Biol. (2017), 44, p. 101.
- Deshaies Nat Chem Biol (2015) 11, p.634.
*Eligibility dependent on project funding