7MSV

Solution Structure of Berberine Bound to a dGMP Fill-in G-Quadruplex in the PDGFR-b Promoter

Summary for 7MSV

• Entry DOI: 10.2210/pdb7msv/pdb
• NMR Information: BMRB: 30907
• Descriptor: DNA (5'-D(*AP*AP*GP*GP*GP*AP*GP*GP*GP*CP*GP*GP*CP*GP*GP*GP*AP*CP*A)-3'), 2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE, BERBERINE (3 entities in total)
• Functional Keywords: g-quadruplex, promoter, guanine metabolite, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 7029.83

Authors

Wang, K.B.,Dickerhoff, J.,Yang, D. (deposition date: 2021-05-12, release date: 2021-10-20, Last modification date: 2024-05-15)

Primary citation

Wang, K.B.,Dickerhoff, J.,Yang, D.
Solution Structure of Ternary Complex of Berberine Bound to a dGMP-Fill-In Vacancy G-Quadruplex Formed in the PDGFR-beta Promoter.
J.Am.Chem.Soc., 143:16549-16555, 2021

PubMed Abstract: The G-quadruplexes (G4s) formed in the 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 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 π-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.

PubMed: 34586799
DOI: 10.1021/jacs.1c06200

Experimental method

SOLUTION NMR