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Publication Abstract from PubMed

Aberrant expression of PDGFR-beta is associated with a number of diseases. The G-quadruplexes (G4s) formed in PDGFR-beta gene promoter are transcriptional modulators and amenable to small molecule targeting. The major G4 formed in the PDGFR-beta gene promoter was previously shown to have a broken G-strand. Herein, we report that the PDGFR-beta 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-beta 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-beta 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-beta vG4.

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.,Wang KB, Dickerhoff J, Wu G, Yang D J Am Chem Soc. 2020 Mar 9. doi: 10.1021/jacs.9b12770. PMID:32101424^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.