Crosslinking Allosteric Sites on the Nucleosome

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.