Newly published in Annual Reviews of Biochemistry: Angus & Alessio's review on E3 Ligase Substrate Specificity for Targeted Protein Degradation

  • Graphical Abstract
  • Figure 1. Native activity and pharmacological hijacking of E3 ligases. Graphical representation of (a) natural, (b) PROTAC-induced, and (c) molecular glue–induced protein degradation by the ubiquitin–proteasome system.
  • Figure 2 Types of substrate recognition by E3 ligases. Graphical representation of type 1, type 2, and type 3 substrate recognition. Modification of either the substrate (type 2), or the E3 ligase (type 3) may be either allosteric or interfacial. The modification may be covalent, noncovalent, or a proteolytic cleavage event.
  • Figure 3 Recognition of substrates by E3 ligases in nature. Substrate receptors and substrates are colored gray and tan, respectively. Hydrogen bonds and ionic interactions are represented as black dotted lines.
  • Figure 4 Ternary cocrystal structures of molecular glue degraders (orange carbons, chemical structure depicted) bound to E3 ligases (gray) and neo-substrates (tan).
  • Figure 5 Ternary complex cocrystal structures of heterobifunctional PROTAC degraders (orange carbons, chemical structure depicted) bound to E3 ligases and neo-substrate targets.

Great review article by Angus.  

Read the full article here.

Read the article open access via the personalized ePrint URL here for the Review in Advance (RIA) version.


Authors: Angus D. Cowan, Alessio Ciulli*

Title: Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory


Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin–proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein–protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics.