Targeted protein degradation (TPD) approaches including PROTAC and molecular glue have revolutionized drug discovery. However, in part due to complication of the ubiquitination and related deubiquitination processes, these ubiquitination-dependent approaches face several challenges in their therapeutic uses. Ubiquitination-independent proteasomal degradation approaches may be a paradigm-shifting solution to key challenges of the field. Recently, midnolin was discovered to promote degradation of non-ubiquitinated proteins by directly recruiting substrates to proteasomes, providing an ideal platform for developing novel TPD strategy through direct 26S proteasome recruitment. However, how midnolin interacts with proteasome and promotes substrate degradation remains enigmatic, hindering its potential application.
This study determined cryo-EM structures of midnolin-proteasome complexes, providing mechanistic insights to midnolin-catalyzed substrate degradation. Based on structural and mechanistic understanding, authors have engineered the midnolin system for targeted degradation of desired substrates, and provide the first proof-of-principle for degrading a non-native therapeutically high-profile target that is otherwise undruggable.
Key findings from the study include:
The midnolin-proteasome pathway degrades proteins in a ubiquitination-independent manner. This study determined cryo-EM structures of midnolin-proteasome complexes and developed engineered midnolin-based targeting chimeras (MidTAC) for targeted protein degradation.
Protein & Cell
Experimental study
Not applicable
Structure-based engineering of the midnolin-proteasome pathway for targeted protein degradation
20-Aug-2025