4.8 Article

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

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 11, 页码 5204-5211

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AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b12770

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  1. National Institutes of Health [R01CA177585, P30CA023168]
  2. Deutsche Forschungsgemeinschaft (German Research Foundation) [427347592]

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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.

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