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

Date

2020

Authors

Ou, Arnold
Schmidberger, Jason
Wilson, Katie
Evans, Cameron
Hargreaves, Jessica A.
Grigg, Melanie
O'Mara, Megan
Swaminathan Iyer, K.
Bond, Charles S.
Smith, Nicole M.

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Volume Title

Publisher

Oxford University Press

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 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.

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Citation

Source

Nucleic Acids Research

Type

Journal article

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Access Statement

Open Access

License Rights

Creative Commons Attribution Non-Commercial License

DOI

10.1093/nar/gkaa262

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