Structural Insights into Electrophiles and Electrophilic Metabolites Sensing and Signaling: The Missing Information

Native reactive electrophile species (RES) are long-recognized regulators of pathophysiology; yet, knowledge surrounding how RES regulate context-specific biology remains limited. The latest technological advances in profiling and precision decoding of RES sensing and signaling have begun to bring about improved understanding of localized RES regulatory paradigms. However, studies in purified systems—prerequisites for gaining structure/function insights—prove challenging. We here introduce emerging chemical biology tools available to probe RES signaling, and the new knowledge that these tools have brought to the field. We next discuss existing structural data of RES-sensor proteins complexed with electrophilic metabolites or small molecule drugs (limited to < 300 Da), including challenges faced in acquiring homogenous RES-bound proteins. We further offer considerations that could promote enhanced understanding of RES regulation derived from three-dimensional structures of RES-modified proteins.