High resolution crystal structure of a KRAS promoter G-quadruplex reveals a dimer with extensive poly-A π-stacking interactions for small-molecule recognition
| Autor: | Jason W. Schmidberger, K. Swaminathan Iyer, Nicole M. Smith, Charles S. Bond, Jessica A Hargreaves, Melanie C Grigg, Arnold Ou, Cameron W. Evans, Megan L. O'Mara, Katie A. Wilson |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
AcademicSubjects/SCI00010
Dimer Molecular Dynamics Simulation Biology Crystallography X-Ray Ligands medicine.disease_cause G-quadruplex Proto-Oncogene Proteins p21(ras) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Structural Biology Genetics medicine Binding site Promoter Regions Genetic neoplasms 030304 developmental biology 0303 health sciences Rational design Water DNA Small molecule digestive system diseases G-Quadruplexes chemistry Docking (molecular) 030220 oncology & carcinogenesis Mutation Biophysics KRAS Poly A Dimerization |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkaa262 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|