Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter.
The c-kit oncogene is an important target in the treatment of gastrointestinal tumors. A potential approach to inhibition of the expression of this gene involves selective stabilization of G-quadruplex structures that may be induced to form in the c-kit promoter region. Here we report on the structure of an unprecedented intramolecular G-quadruplex formed by a G-rich sequence in the c-kit promoter in K+ solution. The structure represents a new folding topology with several unique features. Most strikingly, an isolated guanine is involved in G-tetrad core formation, despite the presence of four three-guanine tracts. There are four loops: two single-residue double-chain-reversal loops, a two-residue loop, and a five-residue stem-loop, which contain base-pairing alignments. This unique structural scaffold provides a highly specific platform for the future design of ligands specifically targeted to the promoter DNA of c-kit.
Phan
Anh Tuân
AT
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. phantuan@ntu.edu.sg
Kuryavyi
Vitaly
V
Burge
Sarah
S
Neidle
Stephen
S
Patel
Dinshaw J
DJ
D004247:DNA / Q000737:chemistry* / Q000235:genetics; D054856:G-Quadruplexes; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012996:Solutions
D012996:Solutions; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit