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Download fileBerberine Molecular Recognition of the Parallel MYC G‑Quadruplex in Solution
journal contribution
posted on 22.10.2021, 17:39 authored by Jonathan Dickerhoff, Nicole Brundridge, Scott A. McLuckey, Danzhou YangThe medicinal natural product berberine
is one of the most actively
studied and pursued G-quadruplex (G4)-ligands. The major G-quadruplex
formed in the promoter region of the MYC oncogene (MycG4) is an attractive
drug target and a prominent example and model structure for parallel
G-quadruplexes. G4-targeted berberine derivatives have been actively
developed; however, the analogue design was based on a previous crystal
structure in which berberine binds as a dimer to a parallel G-quadruplex.
Herein, we show that in solution, the binding mode and stoichiometry
of berberine are substantially different from the crystal structure:
berberine binds as a monomer to MycG4 using a base-recruitment mechanism
with a reversed orientation in that the positively charged convex
side is actually positioned above the tetrad center. Our structure
provides a physiologically relevant basis for the future structure-based
rational design of G4-targeted berberine derivatives, and this study
demonstrates that it is crucial to validate the ligand–DNA
interactions.
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physiologically relevant basisattractive drug targettargeted berberine derivativesberberine molecular recognitiong4 )- ligandsprevious crystal structurebased rational designcrystal structureanalogue designberberine bindsstructure providesmodel structurefuture structuretetrad centersubstantially differentstudy demonstratesreversed orientationrecruitment mechanismpursued gpromoter regionprominent exampleparallel gmyc oncogenemajor gbinding modeactually positionedactively studiedactively developed