title: Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter.
abstract: 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.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. phantuan@ntu.edu.sg
authors.forename: Anh Tuân
authors.initials: AT
authors.lastname: Phan
authors.forename: Vitaly
authors.initials: V
authors.lastname: Kuryavyi
authors.forename: Sarah
authors.initials: S
authors.lastname: Burge
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: 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
chemical_list: D012996:Solutions; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit