title: Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence.
abstract: RET protein functions as a receptor-type tyrosine kinase and has been found to be aberrantly expressed in a wide range of human diseases. A highly GC-rich region upstream of the promoter plays an important role in the transcriptional regulation of RET. Here, we report the NMR solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K(+) solution. The overall G-quadruplex is composed of three stacked G-tetrad and four syn guanines, which shows distinct features for all parallel-stranded folding topology. The core structure contains one G-tetrad with all syn guanines and two other with all anti-guanines. There are three double-chain reversal loops: the first and the third loops are made of 3 nt G-C-G segments, while the second one contains only 1 nt C10. These loops interact with the core G-tetrads in a specific way that defines and stabilizes the overall G-quadruplex structure and their conformations are in accord with the experimental mutations. The distinct RET promoter G-quadruplex structure suggests that it can be specifically involved in gene regulation and can be an attractive target for pathway-specific drug design.
authors.affiliation: State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. tongxt@mail.sioc.ac.cn
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Tong
authors.forename: Wenxian
authors.initials: W
authors.lastname: Lan
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Houming
authors.initials: H
authors.lastname: Wu
authors.forename: Maili
authors.initials: M
authors.lastname: Liu
authors.forename: Chunyang
authors.initials: C
authors.lastname: Cao
mesh_terms: D002942:Circular Dichroism; D054856:G-Quadruplexes; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011188:Potassium / Q000737:chemistry; D011401:Promoter Regions, Genetic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; D011188:Potassium