Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Sarath Ramachandran, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)
49 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)110-119
Number of pages10
JournalCurrent Opinion in Structural Biology
Volume67
Early online date30 Nov 2020
DOIs
Publication statusPublished - Apr 2021

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