TY - JOUR
T1 - Building ubiquitination machineries
T2 - E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues
AU - Ramachandran, Sarath
AU - Ciulli, Alessio
N1 - Funding Information:
The Ciulli laboratory receives or has received sponsored research support from Amphista Therapeutics, Boehringer Ingelheim, Eisai, Nurix Therapeutics, and Ono Pharmaceutical. A.C. is a scientific founder, shareholder, director and consultant of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms.
Funding Information:
Research in the Ciulli laboratory on E3 ubiquitin ligases and PROTACs receives or has received funding from the European Research Council ( ERC , Starting Grant ERC-2012-StG-311460 DrugE3CRLs) and the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement no. 875510 (EUbOPEN project). The IMI2 Join Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, EFPIA companies and Associated Partners: KTH, OICR, Diamond and McGill.
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096865540&partnerID=8YFLogxK
U2 - 10.1016/j.sbi.2020.10.009
DO - 10.1016/j.sbi.2020.10.009
M3 - Review article
C2 - 33271439
SN - 0959-440X
VL - 67
SP - 110
EP - 119
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
ER -