DSSR-derived G-quadruplex features in PDB entry 6v0l
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.
- Pdgfr-b promoter forms a g-vacancy quadruplex that can be complemented by dgmp: molecular structure and recognition of guanine derivatives and metabolites
- Wang, K.B., Dickerhoff, J., Wu, G., Yang, D.: (2020) "PDGFR-beta Promoter Forms a Vacancy G-Quadruplex that Can Be Filled in by dGMP: Solution Structure and Molecular Recognition of Guanine Metabolites and Drugs." J.Am.Chem.Soc., 142, 5204-5211.
- Aberrant expression of PDGFR-β is associated with a number of diseases. The G-quadruplexes (G4s) formed in PDGFR-β gene promoter are transcriptional modulators and amenable to small molecule targeting. The major G4 formed in the PDGFR-β gene promoter was previously shown to have a broken G-strand. Herein, we report that the PDGFR-β gene promoter sequence forms a vacancy G-quadruplex (vG4) which can be filled in and stabilized by physiologically relevant guanine metabolites, such as dGMP, GMP, and cGMP, as well as guanine-derivative drugs. We determined the NMR structure of the dGMP-fill-in PDGFR-β vG4 in K+ solution. This is the first structure of a guanine-metabolite-fill-in vG4 based on a human gene promoter sequence. Our structure and systematic analysis elucidate the contributions of Hoogsten hydrogen bonds, sugar, and phosphate moieties to the specific G-vacancy fill-in. Intriguingly, an equilibrium of 3'- and 5'-end vG4s is present in the PDGFR-β promoter sequence, and dGMP favors the 5'-end fill-in. Guanine metabolites and drugs were tested and showed a conserved selectivity for the 5'-vacancy, except for cGMP. cGMP binds both the 3'- and 5'-end vG4s and forms two fill-in G4s with similar population. Significantly, guanine metabolites are involved in many physiological and pathological processes in human cells; thus, our results provide a structural basis to understand their potential regulatory functions by interaction with promoter vG4s. Moreover, the NMR structure can guide rational design of ligands that target the PDGFR-β vG4.
- G4 notes
- 3 G-tetrads, 1 G4 helix, 1 G4 stem · 2(-P-P-P), parallel(4+0), UUUU
1 glyco-bond=---- groove=---- planarity=0.480 type=other nts=4 GGgG X.DG3,X.DG7,X.DGP101,X.DG14 2 glyco-bond=---- groove=---- planarity=0.296 type=bowl-2 nts=4 GGGG X.DG4,X.DG8,X.DG11,X.DG15 3 glyco-bond=---- groove=---- planarity=0.344 type=bowl nts=4 GGGG X.DG5,X.DG9,X.DG12,X.DG16