Exploring alternate ubiquitin ligase as the degrader of proteolysis-targeting chimera system

A Biotechnology and Biological Sciences Research Council (BBSRC) Collaborative Training Partnership (CTP) PhD studentship is available in Prof. Danny Huang’s laboratory at the CRUK Beatson Institute in partnership with AstraZeneca. The studentship is funded for four years where the student will carry out research at Prof. Huang’s laboratory with 3-6 months placement at AstraZeneca. The research topic focuses on exploring alternate ubiquitin ligase as the degrader of proteolysis-targeting chimera system.

Proteolysis-targeting chimera (PROTAC) technology has emerged as new modality in drug development for therapeutics. PROTACs are bifunctional molecules that consist of two distinct ligands connected by a linker, where one ligand binds to an ubiquitin ligase (E3) and the other binds to a protein of interest (POI) that is not a natural substrate of this E3. In this manner, a PROTAC can bring an E3 and a POI into proximity such that upon recruitment of E2 ubiquitin conjugating enzyme thioesterified with ubiquitin (E2~Ub), the E3 can promote ubiquitination of the POI and target it for degradation by the proteasome. Despite more than 600 E3s in humans, only a few select E3s such as cereblon, VHL, MDM2 and IAP, where existing ligands are available, have been utilised in PROTACs. A productive ubiquitination event requires proper presentation of the substrate lysine sidechains by the E3 to the E2~Ub. As PROTACs function by bringing a non-natural POI and E3 into proximity, the geometry of E3, POI and E2~Ub often poses a challenge for efficient ubiquitination. While modification of the linker chemistry and lengths have been shown to enable ubiquitination for some targets, the availability of degrader E3s remains a limitation of this technology.

The studentship will examine other E3s and assess their feasibility as a PROTAC degrader E3. This will involve tagging POI with novel peptides identified in Prof. Huang’s laboratory that bind selectively to some E3s to establish ubiquitination and degradation both in vitro and in cells. The successful candidate will apply structural, biochemical and cell biology to elucidate the mechanism of degradation.

For informal enquiries or further details on the project, please email Prof. Danny Huang ([Email Address Removed])

The Cancer Research UK Beatson Institute in Glasgow is one of the world-leading centres for cancer research. The Institute provides an outstanding research environment, underpinned by state-of-the-art core services and advanced technologies with special emphasis on imaging, metabolomics and in vivo models of cancer.

To apply, please click on the ’Institution website’ button in thed right-hand menu, which will take you to the Beatson Institute website where you should fill in the application form. Please do not email your CV.