Native Mass Spectrometry: Insights and Opportunities for Targeted Protein Degradation

Native mass spectrometry (nMS) is one of the most powerful biophysical methods for the direct observation of noncovalent protein interactions with both small molecules and other proteins. With the advent of targeted protein degradation (TPD), nMS is now emerging as a compelling approach to characterize the multiple fundamental interactions that underpin the TPD mechanism. Specifically, nMS enables the simultaneous observation of the multiple binary and ternary complexes [i.e., all combinations of E3 ligase, target protein of interest, and small molecule proximity-inducing reagents (such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues)], formed as part of the TPD equilibrium; this is not possible with any other biophysical method. In this paper we overview the proof-of-concept applications of nMS within the field of TPD and demonstrate how it is providing researchers with critical insight into the systems under study. We also provide an outlook on the scope and future opportunities offered by nMS as a core and agnostic biophysical tool for advancing research developments in TPD.