Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry

Abstract

Molecular glues are powerful tools for the control of protein-protein interactions. Yet, the mechanisms underlying multi-component protein complex formation remain poorly understood. Native mass spectrometry (MS) detects multiple protein species...

Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation

“…Additionally, it will be very exciting to explore nMS-based TPD studies with nonmammalian systems particularly for infectious diseases where drug resistance is a significant challenge. Finally, while protein degradation was the phenotypic effect of the proximity-inducing agents discussed herein, there are other proximity-inducing agents that deliver alternate cellular outcomes where nMS could also make a valuable contribution to the characterization of these multicomponent biomolecular systems. − The authors of the highlighted case studies all suggest that nMS will play a crucial role in the next frontier of degrader design and development, in part due to the extreme wealth of knowledge that is garnered, and it will be exciting to witness the future impacts that nMS will have on the field.…”

Native mass spectrometry of complexes formed by molecular glues reveals stoichiometric rearrangement of E3 ligases

“…nMS has previously been used to predict the efficacy of PROTACs, 28 to analyse complexes formed between MGs and model peptides, 21 and to elucidate the contributions of covalent versus non-covalent binding events that govern aldehyde-based covalent molecular glue activity. 29 A recent preprint by our group 30 and work published by Huang et al . 31 demonstrates the efficacy of nMS to MGs and multimeric E3 complexes.…”