4WU9

Structure of cisPtNAP-NCP145

Summary for 4WU9

• Entry DOI: 10.2210/pdb4wu9/pdb
• Related: 4WU8
• Descriptor: Histone H3.2, Histone H4, Histone H2A type 1, ... (10 entities in total)
• Functional Keywords: nucleosome, platinum drug targeting, structural protein-dna complex, structural protein/dna
• Biological source: Xenopus laevis (African clawed frog); More
• Cellular location: Nucleus: P84233 P62799 P06897 P02281
• Total number of polymer chains: 10
• Total formula weight: 200091.16

Authors

Chua, E.Y.D.,Davey, G.E.,Chin, C.F.,Droge, P.,Ang, W.H.,Davey, C.A. (deposition date: 2014-10-31, release date: 2015-09-02, Last modification date: 2024-03-20)

Primary citation

Chua, E.Y.,Davey, G.E.,Chin, C.F.,Droge, P.,Ang, W.H.,Davey, C.A.
Stereochemical control of nucleosome targeting by platinum-intercalator antitumor agents.
Nucleic Acids Res., 43:5284-5296, 2015

PubMed 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.

PubMed: 25916851
DOI: 10.1093/nar/gkv356

Experimental method

X-RAY DIFFRACTION (2.6 Å)