PDBsum entry 5dnm

Structural protein/DNA

PDB id: 5dnm

Contents

Protein chains

97 a.a.

82 a.a.

106 a.a.

95 a.a.

87 a.a.

DNA/RNA

Ligands

SO4 ×3

RAX ×2

Metals

_MG

PDB id:

5dnm

Name:

Structural protein/DNA

Title:

Nucleosome core particle containing adducts of ruthenium(ii)-toluene pta complex

Structure:

Histone h3.2. Chain: a, e. Engineered: yes. Histone h4. Chain: b, f. Engineered: yes. Histone h2a. Chain: c, g. Engineered: yes.

Source:

Xenopus laevis. African clawed frog. Organism_taxid: 8355. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: hist1h2aj, loc494591. Synthetic: yes. Synthetic construct. Organism_taxid: 32630.

Resolution:

2.81Å R-factor: 0.209 R-free: 0.241

Authors:

Z.Adhireksan,R.Muhammad,C.A.Davey

Key ref:

Z.Adhireksan et al. (2017). Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nat Commun, 8, 14860. PubMed id: 28358030

Date:

10-Sep-15 Release date: 14-Sep-16

Protein chains

P84233  (H32_XENLA) -  Histone H3.2 from Xenopus laevis

Seq: 136 a.a.

Struc: 97 a.a.*

Protein chain

P62799  (H4_XENLA) -  Histone H4 from Xenopus laevis

Seq: 103 a.a.

Struc: 82 a.a.

Protein chains

P06897  (H2A1_XENLA) -  Histone H2A type 1 from Xenopus laevis

Seq: 130 a.a.

Struc: 106 a.a.*

Protein chains

P02281  (H2B11_XENLA) -  Histone H2B 1.1 from Xenopus laevis

Seq: 126 a.a.

Struc: 95 a.a.*

Protein chain

P62799  (H4_XENLA) -  Histone H4 from Xenopus laevis

Seq: 103 a.a.

Struc: 87 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DNA/RNA chains

A-T-C-A-A-T-A-T-C-C-A-C-C-T-G-C-A-G-A-T-A-C-T-A-C-C-A-A-A-A-G-T-G-T-A-T-T-T-G- 145 bases

A-T-C-A-A-T-A-T-C-C-A-C-C-T-G-C-A-G-A-T-A-C-T-A-C-C-A-A-A-A-G-T-G-T-A-T-T-T-G- 145 bases

Nat Commun 8:14860 (2017)

PubMed id: 28358030

Allosteric cross-talk in chromatin can mediate drug-drug synergy.

Z.Adhireksan, G.Palermo, T.Riedel, Z.Ma, R.Muhammad, U.Rothlisberger, P.J.Dyson, C.A.Davey.

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.