6WCK

KRAS G-quadruplex G16T mutant with Bromo Uracil replacing T8 and T16.

Summary for 6WCK

• Entry DOI: 10.2210/pdb6wck/pdb
• Related: 6n65
• Descriptor: DNA (5'-D(*AP*GP*GP*GP*CP*GP*GP*(BRU)P*GP*TP*GP*GP*GP*AP*AP*(BRU)P*AP*GP*GP*GP*AP*A)-3'), POTASSIUM ION (3 entities in total)
• Functional Keywords: kras, g-quadruplex, promoter sequence, g16t mutant, bromouracil, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 14428.00

Authors

Schmidberger, J.W.,Ou, A.,Smith, N.M.,Iyer, K.S.,Bond, C.S. (deposition date: 2020-03-30, release date: 2020-04-15, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.801 Å)