Solution Structure of Ternary Complex of Berberine Bound to a dGMP-Fill-In Vacancy G-Quadruplex Formed in the PDGFR-β Promoter

Kai Bo Wang, Jonathan Dickerhoff, Danzhou Yang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The G-quadruplexes (G4s) formed in the PDGFR-β gene promoter are transcriptional modulators and amenable to small-molecule targeting. Berberine (BER), a clinically important natural isoquinoline alkaloid, has gained increasing attention due to its potential as anticancer drug. We previously showed that the PDGFR-β gene promoter forms a unique vacancy G4 (vG4) that can be filled in and stabilized by guanine metabolites, such as dGMP. Herein, we report the high-resolution NMR structure of a ternary complex of berberine bound to the dGMP-fill-in PDGFR-β vG4 in potassium solution. This is the first small-molecule complex structure of a fill-in vG4. This ternary complex has a 2:1:1 binding stoichiometry with a berberine molecule bound at each the 5′- and 3′-end of the 5′-dGMP-fill-in PDGFR-β vG4. Each berberine recruits the adjacent adenine residue from the 5′- or 3′-flanking sequence to form a "quasi-triad plane"that covers the external G-tetrad of the fill-in vG4, respectively. Significantly, berberine covers and stabilizes the fill-in dGMP. The binding of berberine involves both pi;-stacking and electrostatic interactions, and the fill-in dGMP is covered and well-protected by berberine. The NMR structure can guide rational design of berberine analogues that target the PDGFR-β vG4 or dGMP-fill-in vG4. Moreover, our structure provides a molecular basis for designing small-molecule guanine conjugates to target vG4s.

Original languageEnglish (US)
Pages (from-to)16549-16555
Number of pages7
JournalJournal of the American Chemical Society
Volume143
Issue number40
DOIs
StatePublished - Oct 13 2021

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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