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Updated: Nov 27, 2025

In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and
Sarath Ramachandran1, Alessio Ciulli1
1School of Life Sciences, University of Dundee, Division of Biological Chemistry and Drug Discovery, James Black Centre, Dow Street, Dundee DD1 5EH, United Kingdom.
Abstract:
E3 ubiquitin ligase machineries are emerging as attractive therapeutic targets because they confer specificity to substrate ubiquitination and can be hijacked for targeted protein degradation. In this review, we bring to focus our current structural understanding of E3 ligase complexes, in particular the multi-subunit cullin RING ligases, and modulation thereof by small-molecule glues and PROTAC degraders. We highlight recent advances in elucidating the modular assembly of E3 ligase machineries, their diverse substrate and degron recognition mechanisms, and how these structural features impact on ligase function. We then outline the emergence of structures of E3 ligases bound to neo-substrates and degrader molecules, and highlight the importance of studying such ternary complexes for structure-based degrader design.
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