6N65

KRAS G-quadruplex G16T mutant.

6N65 の概要

• エントリーDOI: 10.2210/pdb6n65/pdb
• 分子名称: KRAS G-quadruplex G16T mutant, POTASSIUM ION (3 entities in total)
• 機能のキーワード: kras, g-quadruplex, promoter sequence, g16t mutant, dna
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 14168.52

構造登録者

Schmidberger, J.W.,Ou, A.,Smith, N.M.,Iyer, K.S.,Bond, C.S. (登録日: 2018-11-25, 公開日: 2020-04-15, 最終更新日: 2023-10-11)

主引用文献

Ou, A.,Schmidberger, J.W.,Wilson, K.A.,Evans, C.W.,Hargreaves, J.A.,Grigg, M.,O'Mara, M.L.,Iyer, K.S.,Bond, C.S.,Smith, N.M.
High resolution crystal structure of a KRAS promoter G-quadruplex reveals a dimer with extensive poly-A pi-stacking interactions for small-molecule recognition.
Nucleic Acids Res., 48:5766-5776, 2020

PubMed Abstract: Aberrant KRAS signaling is a driver of many cancers and yet remains an elusive target for drug therapy. The nuclease hypersensitive element of the KRAS promoter has been reported to form secondary DNA structures called G-quadruplexes (G4s) which may play important roles in regulating KRAS expression, and has spurred interest in structural elucidation studies of the KRAS G-quadruplexes. Here, we report the first high-resolution crystal structure (1.6 Å) of a KRAS G-quadruplex as a 5'-head-to-head dimer with extensive poly-A π-stacking interactions observed across the dimer. Molecular dynamics simulations confirmed that the poly-A π-stacking interactions are also maintained in the G4 monomers. Docking and molecular dynamics simulations with two G4 ligands that display high stabilization of the KRAS G4 indicated the poly-A loop was a binding site for these ligands in addition to the 5'-G-tetrad. Given sequence and structural variability in the loop regions provide the opportunity for small-molecule targeting of specific G4s, we envisage this high-resolution crystal structure for the KRAS G-quadruplex will aid in the rational design of ligands to selectively target KRAS.

PubMed: 32313953
DOI: 10.1093/nar/gkaa262

実験手法

X-RAY DIFFRACTION (1.6 Å)