PDBsum entry 4wu8

Structural protein/DNA

PDB id: 4wu8

Contents

Protein chains

96 a.a.

82 a.a.

106 a.a.

95 a.a.

87 a.a.

DNA/RNA

Ligands

CX3 ×2

SO4 ×2

Metals

_MG

Waters ×36

PDB id:

4wu8

Name:

Structural protein/DNA

Title:

Structure of trptnap-ncp145

Structure:

DNA (145-mer). Chain: i. Engineered: yes. DNA (145-mer). Chain: j. Engineered: yes. Histone h3.2. Chain: a, e. Engineered: yes.

Source:

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

Resolution:

2.45Å R-factor: 0.215 R-free: 0.263

Authors:

E.Y.D.Chua,C.A.Davey

Key ref:

E.Y.Chua et al. (2015). Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents. Nucleic Acids Res, 43, 5284-5296. PubMed id: 25916851 DOI: 10.1093/nar/gkv356

Date:

31-Oct-14 Release date: 02-Sep-15

Protein chains

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

Seq: 136 a.a.

Struc: 96 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

Enzyme reactions

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

DOI no: 10.1093/nar/gkv356

Nucleic Acids Res 43:5284-5296 (2015)

PubMed id: 25916851

Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents.

E.Y.Chua, G.E.Davey, C.F.Chin, P.Dröge, W.H.Ang, C.A.Davey.

ABSTRACT

Platinum-based anticancer drugs act therapeutically by forming DNA adducts, but suffer from severe toxicity and resistance problems, which have not been overcome in spite of decades of research. And yet defined chromatin targets have generally not been considered in the drug development process. Here we designed novel platinum-intercalator species to target a highly deformed DNA site near the nucleosome center. Between two seemingly similar structural isomers, we find a striking difference in DNA site selectivity in vitro, which comes about from stereochemical constraints that limit the reactivity of the trans isomer to special DNA sequence elements while still allowing the cis isomer to efficiently form adducts at internal sites in the nucleosome core. This gives the potential for controlling nucleosome site targeting in vivo, which would engender sensitivity to epigenetic distinctions and in particular cell type/status-dependent differences in nucleosome positioning. Moreover, while both compounds yield very similar DNA-adduct structures and display antitumor cell activity rivalling that of cisplatin, the cis isomer, relative to the trans, has a much more rapid cytotoxic effect and distinct impact on cell function. The novel stereochemical principles for controlling DNA site selectivity we discovered could aid in the design of improved site discriminating agents.