PDBsum entry 4kgc

Structural protein/DNA

PDB id: 4kgc

Contents

Protein chains

97 a.a.

82 a.a.

106 a.a.

95 a.a.

87 a.a.

DNA/RNA

Ligands

HRU ×4

SO4 ×3

Metals

_MG

PDB id:

4kgc

Name:

Structural protein/DNA

Title:

Nucleosome core particle containing (eta6-p-cymene)-(1, 2- ethylenediamine)-ruthenium

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. Clawed frog,common platanna,platanna. Organism_taxid: 8355. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: hist1h2aj, loc494591. Synthetic: yes. Synthetic construct. Organism_taxid: 32630.

Resolution:

2.69Å R-factor: 0.248 R-free: 0.282

Authors:

Z.Adhireksan,C.A.Davey

Key ref:

Z.Adhireksan et al. (2014). Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity. Nat Commun, 5, 3462. PubMed id: 24637564 DOI: 10.1038/ncomms4462

Date:

29-Apr-13 Release date: 26-Mar-14

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

Q6AZJ8  (Q6AZJ8_XENLA) -  Histone H2A 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 1 residue position (black cross)

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

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H: E.C.?

DOI no: 10.1038/ncomms4462

Nat Commun 5:3462 (2014)

PubMed id: 24637564

Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity.

Z.Adhireksan, G.E.Davey, P.Campomanes, M.Groessl, C.M.Clavel, H.Yu, A.A.Nazarov, C.H.Yeo, W.H.Ang, P.Dröge, U.Rothlisberger, P.J.Dyson, C.A.Davey.

ABSTRACT

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.