Issue 24, 2023

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 simultaneously, providing an entry to elucidate these mechanisms. Here, for the first time, covalent molecular glue stabilization was kinetically investigated by combining native MS with biophysical and structural techniques. This approach elucidated the stoichiometry of a multi-component protein–ligand complex, the assembly order, and the contributions of covalent versus non-covalent binding events that govern molecular glue activity. Aldehyde-based molecular glue activity is initially regulated by cooperative non-covalent binding, followed by slow covalent ligation, further enhancing stabilization. This study provides a framework to investigate the mechanisms of covalent small molecule ligation and informs (covalent) molecular glue development.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
04 apr 2023
Accepted
30 may 2023
First published
31 may 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 6756-6762

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

C. J. A. Verhoef, D. F. Kay, L. van Dijck, R. G. Doveston, L. Brunsveld, A. C. Leney and P. J. Cossar, Chem. Sci., 2023, 14, 6756 DOI: 10.1039/D3SC01732J

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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