Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 44, Pages 15660-15664Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201906423
Keywords
allostery; bioinorganic chemistry; macromolecular crystallography; molecular dynamics simulations; nucleosome structure
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Funding
- Singapore Ministry of Education Academic Research Fund Tier 1 Programme [2017-T1-002-020]
- Singapore Ministry of Education Academic Research Fund Tier 2 Programme [MOE2015-T2-2-089]
- Singapore Ministry of Education Academic Research Fund Tier 3 Programme [MOE2012-T3-1-001]
- Swiss National Supercomputing Center
- European Union [730872]
- Swiss National Science Foundation
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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.
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