Structures of 1:1 and 2:1 complexes of BMVC and MYC promoter G-quadruplex reveal a mechanism of ligand conformation adjustment for G4-recognition

Wenting Liu, Clement Lin, Guanhui Wu, Jixun Dai, Ta Chau Chang, Danzhou Yang

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 languageEnglish (US)
Pages (from-to)11931-11942
Number of pages12
JournalNucleic acids research
Volume47
Issue number22
DOIs
StatePublished - Dec 16 2019

ASJC Scopus subject areas

  • Genetics

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