4DAQ

Crystal structure of an intramolecular human telomeric DNA G-quadruplex 21-mer bound by the naphthalene diimide compound BMSG-SH-3

4DAQ の概要

• エントリーDOI: 10.2210/pdb4daq/pdb
• 関連するPDBエントリー: 3SC8 3T5E 3UYH 4DA3
• 分子名称: DNA (5'-D(*GP*GP*GP*TP*TP*AP*GP*GP*GP*TP*TP*AP*GP*GP*GP*TP*TP*AP*GP*GP*G)-3'), POTASSIUM ION, 2,7-bis[3-(4-methylpiperazin-1-yl)propyl]-4,9-bis{[3-(4-methylpiperazin-1-yl)propyl]amino}benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetrone, ... (4 entities in total)
• 機能のキーワード: intramolecular, ligand-complex, g-quadruplex, dna
• 由来する生物種: Synthetic DNA
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7644.73

構造登録者

Collie, G.W.,Neidle, S. (登録日: 2012-01-13, 公開日: 2013-01-16, 最終更新日: 2023-09-13)

主引用文献

Micco, M.,Collie, G.W.,Dale, A.G.,Ohnmacht, S.A.,Pazitna, I.,Gunaratnam, M.,Reszka, A.P.,Neidle, S.
Structure-based design and evaluation of naphthalene diimide g-quadruplex ligands as telomere targeting agents in pancreatic cancer cells.
J.Med.Chem., 56:2959-2974, 2013

PubMed Abstract: Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1.

PubMed: 23514618
DOI: 10.1021/jm301899y

実験手法

X-RAY DIFFRACTION (2.754 Å)