DSSR-derived G-quadruplex features in PDB entry 6wck
Poster "DSSR-Enabled Automatic Identification and Annotation of G-quadruplexes in the PDB" presented at the RNA2020 online meeting
Citation: before a paper dedicated to the DSSR-G4 module comes out, please cite the 2015 DSSR paper published in Nucleic Acids Research.
- X-ray (1.8 Å)
- Kras G-quadruplex g16t mutant with bromo uracil replacing t8 and t16
- 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.: (2020) "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.
- 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.
- G4 notes
- 6 G-tetrads, 1 G4 helix, 2 G4 stems, 1 G4 coaxial stack · 3(-P-P-P), parallel(4+0), UUUU · coaxial interfaces: 5'/5'
1 glyco-bond=---- groove=---- planarity=0.070 type=planar nts=4 GGGG A.DG2,A.DG6,A.DG11,A.DG18 2 glyco-bond=---- groove=---- planarity=0.119 type=planar nts=4 GGGG A.DG3,A.DG7,A.DG12,A.DG19 3 glyco-bond=---- groove=---- planarity=0.184 type=other nts=4 GGGG A.DG4,A.DG9,A.DG13,A.DG20 4 glyco-bond=---- groove=---- planarity=0.051 type=planar nts=4 GGGG B.DG2,B.DG6,B.DG11,B.DG18 5 glyco-bond=---- groove=---- planarity=0.121 type=planar nts=4 GGGG B.DG3,B.DG7,B.DG12,B.DG19 6 glyco-bond=---- groove=---- planarity=0.198 type=other nts=4 GGGG B.DG4,B.DG9,B.DG13,B.DG20
Helix#1, 6 G-tetrad layers, inter-molecular, with 2 stems
Stem#1, 3 G-tetrad layers, 3 loops, INTRA-molecular, UUUU, parallel, 3(-P-P-P), parallel(4+0)
Stem#2, 3 G-tetrad layers, 3 loops, INTRA-molecular, UUUU, parallel, 3(-P-P-P), parallel(4+0)
1 G4 helix#1 contains 2 G4 stems: [#1,#2] [5'/5']