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Intrinsically disordered proteins (IDPs) remain largely inaccessible to covalent chemical tools due to their structural plasticity and lack of defined pockets. We introduce a bioorthogonal cyclometalated gold(III) platform of monodentate phosphine-supported AuP1-8 complexes that selectively and irreversibly arylate cysteine residues via enhanced Lewis acidity. This platform enables targeting of low-reactivity, buried, or dynamically disordered cysteines across the human proteome. Chemoproteomic, structural, and computational analyses establish an expanded ligandable cysteinome, including transiently helical LLCLL motifs in intrinsically disordered regions (IDRs). Our findings establish a new class of metal-mediated bioorthogonal reagents for proteome-wide cysteine labeling, functional interrogation of disordered proteins, and future therapeutic and diagnostic applications.
Munugoda et al. (Mon,) studied this question.