Abstract: | Targeting defined histone protein sites in chromatin is an emerging therapeutic approach that can potentially be enhanced by allosteric effects within the nucleosome. Here we characterized a novel hetero‐bimetallic compound with a design based on a nucleosomal allostery effect observed earlier for two unrelated drugs—the RuII antimetastasis/antitumor RAPTA‐T and the AuI anti‐arthritic auranofin. The RuII moiety binds specifically to two H2A glutamate residues on the nucleosome acidic patch, allosterically triggering a cascade of structural changes that promote binding of the AuI moiety to selective histidine residues on H3, resulting in cross‐linking sites that are over 35 Å distant. By tethering the H2A‐H2B dimers to the H3‐H4 tetramer, the hetero‐bimetallic compound significantly increases stability of the nucleosome, illustrating its utility as a site‐selective cross‐linking agent. |