Abstract 860: Solution structure of a dGMP fill-in G-quadruplex forms in PDGFR-bpromoter

Platelet-derived growth factor receptor beta (PDGFR-β) is an important cell-surface-receptor tyrosine kinase implicated in PDGF signaling pathways. The PDGFR-β signaling pathway has been demonstrated as an essential component in control of the cellular growth, proliferation, survival, motility and differentiation. Overexpression of PDGFR-β is associated with tumor growth, angiogenesis, and migration, making PDGFR-β an attractive target for anticancer therapeutics. In the PDGFR-β gene promoter, a highly GC-rich proximal promoter region -165 to -139 nt upstream of the transcriptional start site is crucial for basal promoter activity, which can form G-quadruplexes (G4s). These structures can be stabilized by the G4-interactive molecules to inhibit the PDGFR-β transcriptional activity. Our previous structure study showed that the G4 structures formed in the PDGFR-β gene promoter always contain a broken G-strand. The broken-strand structure suggests a possibility of the formation of a G-vacancy-bearing G-quadruplex (GVBQ) structure, which can be complemented and stabilized by guanine and guanine derivatives. Elevated levels of guanine and guanine derivatives/metabolites are found in tumor cells, suggesting that the GVBQs may play important regulatory roles in tumor cell pathological processes, such as PDGFR-β transcriptional regulation. Using NMR, CD, EMSA and DMS footprinting experiments, herein, we contributed the first atomic resolution structure of a dGMP fill-in G4 formed in PDGFR-β gene promoter in potassium solution. Surprisingly, our results showed that solution dGMP preferentially inserts from the 59 end tetrad instead of the G-22 position of the previously determined structure, and maybe in dynamic equilibrium with our previously reported G-quadruplex. The dGMP, like other intramolecular guanines, that forms four Hoogsteen hydrogen bonds with adjacent guanines and stabilizes by electronic coordination with potassium cation as well as the π-π stacking interaction with the middle tetrad guanine. Moreover, a series of guanine derivatives were investigated to fill in this GVBQ, and found that only these derivatives that keep the ability to form Hoogsteen hydrogen bonds in G-tetrad can serve as the substrate, providing insights into designing new guanine derivatives anticancer drugs. Citation Format: Kaibo Wang, Jonathan Dickerhoff, Guanhui Wu, Clement Lin, Danzhou Yang. Solution structure of a dGMP fill-in G-quadruplex forms in PDGFR- b promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 860.