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Crosslinking Allosteric Sites on the Nucleosome

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Batchelor Lucinda K., De Falco Louis, Erlach Thibaud, Sharma Deepti, Adhireksan Zenita, Roethlisberger Ursula, Davey Curt A., Dyson Paul J.,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
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Original article (peer-reviewed)

Journal Angewandte Chemie International Edition
Volume (Issue) 58(44)
Page(s) 15660 - 15664
Title of proceedings Angewandte Chemie International Edition
DOI 10.1002/anie.201906423

Open Access

Type of Open Access Publisher (Gold Open Access)


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-Tand 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 c 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.