DNA sequence recognition by the indolocarbazole antitumor antibiotic AT2433-B1 and its diastereoisomer

被引:38
|
作者
Carrasco, C
Facompré, M
Chisholm, JD
Van Vranken, DL
Wilson, WD
Bailly, C
机构
[1] Ctr Oscar Lambret, Lab Pharmacol Antitumorale, F-59045 Lille, France
[2] IRCL, INSERM, U524, F-59045 Lille, France
[3] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA
[4] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA
[5] Georgia State Univ, Lab Chem & Biol Sci, Atlanta, GA 30303 USA
关键词
D O I
10.1093/nar/30.8.1774
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The antibiotic AT2433-B1 belongs to a therapeutically important class of antitumor agents. This natural product contains an indolocarbazole aglycone connected to a unique disaccharide consisting of a methoxyglucose and an amino sugar subunit, 2,4-dideoxy-4-methylamino-l-xylose. The configuration of the amino sugar distinguishes AT2433-B1 from its diastereoisomer iso-AT2433-B1. Here we have investigated the interaction of these two disaccharide indolocarbazole derivatives with different DNA sequences by means of DNase I footprinting and surface plasmon resonance (SPR). Accurate binding measurements performed at 4 and 25degreesC using the BIAcore SPR method revealed that AT2433-B1 binds considerably more tightly to a hairpin oligomer containing a [CG](4) block than to an oligomer with a central [AT](4) tract. The kinetic analysis shows that the antibiotic dissociates much more slowly from the GC sequence compared to the AT one. Preferential binding of AT2433-B1 to GC-rich sequences in DNA was independently confirmed by DNase I footprinting experiments performed with a 117 bp DNA restriction fragment. The specific binding sequence 5'-AACGCCAG identified from the footprints was then converted into a biotin-labeled DNA hairpin duplex and compound interactions with this specific sequence were characterized by high resolution BIAcore SPR experiments. Such a combined approach provided a detailed understanding of the molecular basis of DNA recognition. The discovery that the glycosyl antibiotic AT2433-B1 preferentially recognizes defined sequences offers novel opportunities for the future design of sequence-specific DNA-reading small molecules.
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页码:1774 / 1781
页数:8
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