6IQ4

Nucleosome core particle cross-linked with a hetero-binuclear molecule possessing RAPTA and gold(I) 4-(diphenylphosphino)benzoic acid groups.

Summary for 6IQ4

• Entry DOI: 10.2210/pdb6iq4/pdb
• Descriptor: Histone H3.1, MAGNESIUM ION, [Ru(eta(6)-p-cymene)Cl-2(pta), ... (12 entities in total)
• Functional Keywords: nucleosome, anticancer, organometallic, cross-link, gold, ruthenium, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 177347.31

Authors

DeFalco, L.,Batchelor, L.K.,Adhireksan, Z.,Dyson, P.J.,Davey, C.A. (deposition date: 2018-11-06, release date: 2019-10-30, Last modification date: 2024-03-27)

Primary citation

Batchelor, L.K.,De Falco, L.,von Erlach, T.,Sharma, D.,Adhireksan, Z.,Roethlisberger, U.,Davey, C.A.,Dyson, P.J.
Crosslinking Allosteric Sites on the Nucleosome.
Angew.Chem.Int.Ed.Engl., 58:15660-15664, 2019

PubMed 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 Ru antimetastasis/antitumor RAPTA-T and the Au anti-arthritic auranofin. The Ru 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 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.

PubMed: 31478581
DOI: 10.1002/anie.201906423

Experimental method

X-RAY DIFFRACTION (2.25 Å)