Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Issue 7 (15th July 2021)

• Record Type: Journal Article
• Authors: Kannt, Aimo; Đikić, Ivan
• Is Part Of: Cell chemical biology. Volume 28:Issue 7(2021)
• Page Start: 1014
• Page End: 1031
• Publication Date: 2021-07-15
• Subjects: E3 ubiquitin ligase -- targeted protein degradation -- PROTAC -- molecular glue -- ubiquitin-proteasome system; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.04.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Efficacy and selectivity of molecules inducing protein degradation depend on their affinity to the target protein but also on the type of E3 ubiquitin ligase that is recruited to trigger proteasomal degradation. While tremendous progress has been made on the former, the latter—the arsenal of E3 ligases that can be hijacked for targeted protein degradation—is still largely unexplored. Only about 2% of the more than 600 E3 ligases have been utilized to date. Exploiting additional E3 ligases that are, for example, selectively expressed in specific tissues or cells, or regulated under certain conditions, can considerably broaden the applicability of molecular degraders as a therapeutic modality. Here, we provide an overview of major classes of E3 ligases, review the enzymes that have been exploited for induced protein degradation and approaches used to identify or design E3 ligands, and highlight challenges and opportunities for targeting new E3 ligases. Graphical abstract: Abstract : Kannt and Đikić give an overview of E3 ubiquitin ligases that have been utilized for induced protein degradation. They outline challenges and opportunities related to targeting additional E3 ligases and summarize approaches and recent technological advances to identify and design new ligands and repurpose E3 ligases for targeted protein degradation.