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 Ru-II antimetastasis/antitumor RAPTA-T and the Au-I anti-arthritic auranofin. The Ru-II 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 Au-I moiety to selective histidine residues on H3, resulting in cross-linking sites that are over 35 angstrom 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.