A proteome-wide atlas of lysine-reactive chemistry

Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule-lysine interactions captured by the entire library. We used these latter 'scout' electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein-RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.

Automated summary

Recent advances in chemical proteomics have identified and characterized a wide range of uncharted aminophilic chemotypes that greatly expand the ligandable lysines in human proteins. Aminophilic electrophiles showed varying proteomic reactivities, from selective interactions with specific lysines to broad engagement with covalent small-molecule-lysine interactions. The study demonstrates the potential of covalent chemistry in targeting functional lysines in the human proteome, perturbing diverse biochemical functions.