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Eastbio PhD Programme: Targeting the MYCBP2 E3 ubiquitin ligase with small molecules


About This PhD Project

Project Description



This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and EU nationals.

Applicants should apply by completing the EASTBIO application form (downloadable from the EASTBIO website) and e-mail to . Candidates should also include their academic transcripts and ensure that they ask their referees to send completed references to . Applicants may wish to explain their motivation for joining the EASTBIO training programme.

E3 ubiquitin ligases are diverse multi-domain and multi-subunit enzymes within the ubiquitin-proteasome system (UPS) that catalyse the transfer of ubiquitin to specific substrate proteins. Targeting of E3 ligases with small molecules is emerging as a frontier goal of chemical biology and drug discovery for two main reasons: 1) the potential to develop chemical tools to allow for enhanced selective intervention in the UPS, compared for example to targeting the proteasome downstream or E1/E2 enzymes upstream in the pathway; 2) the opportunity to leverage E3 ligase targeting ligands to co-opt E3 ligases to induce the degradation of neo-substrate proteins they do not normally bind to. For example, E3 ligase ligands can be incorporated into bifunctional chimeric molecules, also known as proteolysis targeting chimeras (PROTACs), that induce protein ubiquitination and subsequent degradation inside the cell. However, targeting E3 ligases with small molecules is challenging, because of their highly diverse and complex structural features, and because of the need to modulate protein-protein interactions that often involve shallow and difficult-to-target binding sites (1).

The Ciulli lab works on developing E3 ligase targeting ligands and PROTACs. The Ciulli lab has pioneered the structure-guided development of E3 ligase ligands and PROTACs targeting the von Hippel-Lindau (VHL) E3 ligase. They qualified potent and selective VHL inhibitor VH298 as a chemical probe of the VHL-HIF axis in the hypoxia signaling pathway. Moreover, they have shown how the VHL ligands can be successfully conjugated to a variety of protein-targeting ligands, yielding PROTACs active against diverse target proteins in cells and in vivo. Successful examples from the Lab include the BET proteins, chromatin-remodelling complex subunits Brd7/9 and SMARCA2/4, protein kinases as well as E3 ligases VHL and CRBN themselves (2).

The Virdee lab has pioneered the development of novel chemical biology tools for studying the ubiquitin system, with a particular focus on E3 ligases. A key achievement is the development of probes that measure the hallmark trans-thiolation activity of ubiquitin conjugation enzymes. These have been used to gain insights into disease relevant E3regulation and have great biomarker potential for diseases of unmet clinical need. Application of these technologies has led to the identification of a novel class of ubiquitin E3 ligase that has non-lysine ubiquitination activity, exemplified by the E3 ligase MYCBP2. Rigorous characterisation of MYCBP2’s novel mechanism by biochemical methods and crystal structures have shown an unusual mechanism of action that ultimately leads to ubiquitination of the substrate protein on a threonine residue (3).

This project aims to develop small molecule bindersofMYCBP2,and the project will initially focus on the ligase-substrate interaction. It will involve developing the reagents and tools to enable fragment screening and structure-based ligand design, including soakable crystals of the targeted subunit(s), assays for ligand binding and screening, and structure-guided design efforts to optimize the binding affinity and specificity. Once compounds of suitable affinity and physicochemical properties are achieved, we will: 1) test their activity as E3 ligase inhibitors and probes in their own right; 2) design chimeric PROTAC molecules that recruit MYCBP2 to induce ubiquitination of target proteins. Successful development of the project will qualify new chemical tools to probe MYCBP2 biology and untap a potential new E3 ligase for the PROTAC field.

The student will receive outstanding training in multidisciplinary areas in cutting-edge research in fundamental and translational chemical and structural biology from both the Ciulli and Virdee labs.


References

References:

1.Lucas X, Ciulli A. Curr Opin Struct Biol2017; 44:101–10.

2.Maniaci C, Ciulli A. Curr Opin Chem Biol2019; 52:145–56.

3.Pao K-C et al. Nature 2018; 556:381–5.

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