2N96

An unexpected mode of small molecule DNA binding provides the structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A

2N96 の概要

• エントリーDOI: 10.2210/pdb2n96/pdb
• NMR情報: BMRB: 25882
• 分子名称: DNA (5'-D(*GP*CP*TP*AP*TP*AP*GP*C)-3'), (1R,1'R,2S,2'S,3R,3'R,5aR,10aR,11a'S)-2'-[(2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranosyl)oxy]-2,2'-diethyl-11,11 '-dihydrazinyl-6,6',9,9'-tetrahydroxy-4,4',5,5',10,10'-hexaoxo-1,1'-bis{[2,4,6-trideoxy-4-(dimethylamino)-beta-L-arabino -hexopyranosyl]oxy}[2,2',3,3',4,4',5,5',5a,8,10,10',10a,11a'-tetradecahydro-1H,1'H-[3,3'-bibenzo[b]fluorene]]-2-yl 2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranoside (2 entities in total)
• 機能のキーワード: diazofluorene, intercalator, dna
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 6228.70

構造登録者

Woo, C.M.,Li, Z.,Paulson, E.,Herzon, S.B. (登録日: 2015-11-07, 公開日: 2016-06-01, 最終更新日: 2024-05-15)

主引用文献

Woo, C.M.,Li, Z.,Paulson, E.K.,Herzon, S.B.
Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A.
Proc.Natl.Acad.Sci.USA, 113:2851-2856, 2016

PubMed Abstract: (-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C2-symmetric structure that contains two unusual diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC)2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association.

PubMed: 26929332
DOI: 10.1073/pnas.1519846113

実験手法

SOLUTION NMR