Solution Structure of a 2:1 Quindoline鈥揷-MYC G-Quadruplex: Insights into G-Quadruplex-Interactive Small Molecule Drug Design
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- 作者：Jixun Dai ; Megan Carver ; Laurence H. Hurley ; Danzhou Yang
- 刊名：Journal of the American Chemical Society
- 出版年：2011
- 出版时间：November 9, 2011
- 年：2011
- 卷：133
- 期：44
- 页码：17673-17680
- 全文大小：1025K
- 年卷期：v.133,no.44(November 9, 2011)
- ISSN：1520-5126
文摘
Unimolecular parallel-stranded G-quadruplex structures are found to be prevalent in gene promoters. The nuclease hypersensitivity element III1 (NHE III1) of the c-MYC promoter can form transcriptionally active and silenced forms, and the formation of DNA G-quadruplex structures has been shown to be critical for c-MYC transcriptional silencing. The solution structure of a 2:1 quindoline鈥揋-quadruplex complex has been solved and shows unexpected features, including the drug-induced reorientation of the flanking sequences to form a new binding pocket. While both 3鈥?and 5鈥?complexes show overall similar features, there are identifiable differences that emphasize the importance of both stacking and electronic interactions. For the first time, we describe the importance of the shape of the ligand as well as the two flanking bases in determining drug binding specificity. These structures provide important insights for the structure-based rational design of drugs that bind to unimolecular parallel G-quadruplexes commonly found in promoter elements.