5DNN

Nucleosome core particle containing adducts of gold(I)-triethylphosphane and ruthenium(II)-toluene PTA complexes

Summary for 5DNN

• Entry DOI: 10.2210/pdb5dnn/pdb
• Related: 5DNM
• Descriptor: Histone H3.2, dichloro[(1,2,3,4,5,6-eta)-6-methylbenzene]1,3,5-triaza-7lambda~5~-phosphatricyclo[3.3.1.1~3,7~]dec-7-ylruthenium, Histone H4, ... (10 entities in total)
• Functional Keywords: nucleosome, gold antitumour compound, ruthenium antitumour compound, histone binding, structural protein-dna complex, structural protein/dna
• Biological source: Xenopus laevis (African clawed frog); More
• Cellular location: Nucleus: P84233 P62799 P02281
• Total number of polymer chains: 10
• Total formula weight: 199920.43

Authors

Adhireksan, Z.,Ma, Z.,Davey, C.A. (deposition date: 2015-09-10, release date: 2016-09-14, Last modification date: 2023-11-08)

Primary citation

Adhireksan, Z.,Palermo, G.,Riedel, T.,Ma, Z.,Muhammad, R.,Rothlisberger, U.,Dyson, P.J.,Davey, C.A.
Allosteric cross-talk in chromatin can mediate drug-drug synergy
Nat Commun, 8:14860-14860, 2017

PubMed Abstract: Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

PubMed: 28358030
DOI: 10.1038/ncomms14860

Experimental method

X-RAY DIFFRACTION (2.8 Å)