Induction of a remarkable conformational change in a human telomeric sequence by the binding of naphthyridine dimer: Inhibition of the elongation of a telomeric repeat by telomerase

被引:59
作者
Nakatani, K [1 ]
Hagihara, S
Sando, S
Sakamoto, S
Yamaguchi, K
Maesawa, C
Saito, I
机构
[1] Kyoto Univ, Fac Engn, Dept Synthet Chem & Biol Chem, Kyoto 6068501, Japan
[2] Iwate Med Univ, Sch Med, Dept Pathol, Morioka, Iwate 0208505, Japan
[3] Chiba Univ, Ctr Chem Anal, Chiba 2638533, Japan
[4] Japan Sci & Technol Corp, PRESTO, JST, Kawagoe, Saitama 3320012, Japan
关键词
D O I
10.1021/ja027055g
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The binding of a dimeric form of the 2-amino-1,8-naphthyridine derivative (naphthyridine dimer) to a human telomeric sequence, TTAGGG, was investigated by UV melting, CD spectra, and CSI-MS measurements. Both the 9-mer d(TTAGGGTTA) and the 15-mer d(TTAGGGTTAGGGTTA) showed apparent melting temperatures (T-m) of 45.6 and 63.6 degreesC, respectively, in the presence of naphthyridine dimer (30 muM) in sodium cacodylate buffer (50 mM, pH 7,0) containing 100 mM NaCl. The CD spectra at 235 and 255 nm of the 9-mer increased in intensity accompanied with strong induced CDs at 285 and 340 nm upon complex formation with naphthyridine dimer. UV titration of the binding of naphthyridine dimer to the 9-mer at 320 nm showed a hypochromism of the spectra, A Scatchard plot of the data showed the presence of multiple binding sites with different association constants. Cold spray ionization mass spectrometry of the complex between naphthyridine dimer and the 9-mer clearly showed that one to three molecules of the ligand bound to the dimer duplex of the 9-mer. Telomeric repeat elongation assay showed that the binding of naphthyridine dimer to the telomeric sequence inhibits the elongation of the sequence by telomerase.
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收藏
页码:662 / 666
页数:5
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