Abstract
BMVC is the first fluorescent probe designed to detect G-quadruplexes (G4s) in vivo. The MYC oncogene promoter forms a G4 (MycG4) which acts as a transcription silencer. Here, we report the high-affinity and specific binding of BMVC to MycG4 with unusual slow-exchange rates on the NMR timescale. We also show that BMVC represses MYC in cancer cells. We determined the solution structures of the 1:1 and 2:1 BMVC-MycG4 complexes. BMVC first binds the 5′-end of MycG4 to form a 1:1 complex with a well-defined structure. At higher ratio, BMVC also binds the 3′-end to form a second complex. In both complexes, the crescent-shaped BMVC recruits a flanking DNA residue to form a BMVC-base plane stacking over the external G-tetrad. Remarkably, BMVC adjusts its conformation to a contracted form to match the G-tetrad for an optimal stacking interaction. This is the first structural example showing the importance of ligand conformational adjustment in G4 recognition. BMVC binds the more accessible 5′-end with higher affinity, whereas sequence specificity is present at the weaker-binding 3′-site. Our structures provide insights into specific recognition of MycG4 by BMVC and useful information for design of G4-targeted anticancer drugs and fluorescent probes.
Original language | English (US) |
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Pages (from-to) | 11931-11942 |
Number of pages | 12 |
Journal | Nucleic acids research |
Volume | 47 |
Issue number | 22 |
DOIs | |
State | Published - Dec 16 2019 |
ASJC Scopus subject areas
- Genetics
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NMR structure of the 1:1 complex of a carbazole derivative BMVC bound to c-MYC G-quadruplex
Liu, W. (Contributor), Lin, C. (Contributor), Wu, G. (Contributor), Dai, J. (Contributor), Chang, T.-C. (Contributor) & Yang, D. (Contributor), Protein Data Bank (PDB), Oct 30 2019
DOI: 10.2210/pdb6JJ0/pdb, https://www.wwpdb.org/pdb?id=pdb_00006jj0
Dataset
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NMR structure of the 2:1 complex of a carbazole derivative BMVC bound to c-MYC G-quadruplex
Liu, W. (Contributor), Lin, C. (Contributor), Wu, G. (Contributor), Dai, J. (Contributor), Chang, T.-C. (Contributor) & Yang, D. (Contributor), Protein Data Bank (PDB), Oct 23 2019
DOI: 10.2210/pdb6O2L/pdb, https://www.wwpdb.org/pdb?id=pdb_00006o2l
Dataset