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PDGFR-β Promoter Forms a Vacancy G-Quadruplex that Can Be Filled in by dGMP: Solution Structure and Molecular Recognition of Guanine Metabolites and Drugs

  • Kai-Bo Wang
    Kai-Bo Wang
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
    More by Kai-Bo Wang
  • Jonathan Dickerhoff
    Jonathan Dickerhoff
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
  • Guanhui Wu
    Guanhui Wu
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States
    More by Guanhui Wu
  • , and 
  • Danzhou Yang*
    Danzhou Yang
    Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy,  Purdue Center for Cancer Research  and  Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
    *[email protected]
    More by Danzhou Yang
Cite this: J. Am. Chem. Soc. 2020, 142, 11, 5204–5211
Publication Date (Web):February 26, 2020
https://doi.org/10.1021/jacs.9b12770
Copyright © 2020 American Chemical Society
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Abstract

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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.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b12770.

  • Chemical structures of tested guanine metabolites, drugs, and derivatives, DNA sequences, tables of proton chemical shifts and NOEs, 1H NMR titration spectra of various guanine derivatives, DMS footprinting, EMSA, variable temperature 1H NMR spectra, 15N-edited and 13C-edited NMR spectra, 1H–13C-HSQC, 2D-NOESY, superposition of 10 lowest energy structures, 650 ns MD simulation, MST data, and CD spectra (PDF)

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This article is cited by 26 publications.

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