High resolution crystal structure of a KRAS promoter G-quadruplex reveals a dimer with extensive poly-A π-stacking interactions for small-molecule recognition

Arnold Ou, Jason Schmidberger, Katie Wilson, Cameron Evans, Jessica Hargreaves, Melanie Grigg, Megan O'Mara, Killugudi Swaminatha Iyer, Charlie Bond, Nicole Smith

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 A ̊ ) of a KRAS G-quadruplex as a 5′-head-to-head dimer with extensive poly-A ﰀ-stacking interactions observed across the dimer. Molecular dynamics simulations confirmed that the poly-A ﰀ-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 indi- cated the poly-A loop was a binding site for these lig- ands in addition to the 5′-G-tetrad. Given sequence and structural variability in the loop regions provide the opportunity for small-molecule targeting of spe- cific 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.
Original languageEnglish
Pages (from-to)5766-5776
Number of pages11
JournalNucleic Acids Research
Volume48
Issue number10
DOIs
Publication statusPublished - 4 Jun 2020

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