7N7D

Solution structure of the MYC promoter G-quadruplex in complex with berberine: conformer A

Summary for 7N7D

• Entry DOI: 10.2210/pdb7n7d/pdb
• NMR Information: BMRB: 30923
• Descriptor: Myc2345, BERBERINE (2 entities in total)
• Functional Keywords: g-quadruplex dna, drug-dna complex, berberine, cancer, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 7706.24

Authors

Dickerhoff, J.,Yang, D. (deposition date: 2021-06-10, release date: 2021-11-03, Last modification date: 2024-05-15)

Primary citation

Dickerhoff, J.,Brundridge, N.,McLuckey, S.A.,Yang, D.
Berberine Molecular Recognition of the Parallel MYC G-Quadruplex in Solution.
J.Med.Chem., 64:16205-16212, 2021

PubMed Abstract: The 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.

PubMed: 34677968
DOI: 10.1021/acs.jmedchem.1c01508

Experimental method

SOLUTION NMR