Abstract
DNA G-Quadruplexes (G4s) formed in oncogene promoters regulate transcription. The oncogene MYC promoter G4 (MycG4) is the most prevalent G4 in human cancers. However, the most studied MycG4 sequence bears a mutated 3′-residue crucial for ligand recognition. Here, we report a new drug-like small molecule PEQ without a large aromatic moiety that specifically binds MycG4. We determined the NMR solution structures of the wild-type MycG4 and its 2:1 PEQ complex, as well as the structure of the 2:1 PEQ complex of the widely used mutant MycG4. Comparison of the two complex structures demonstrates specific molecular recognition of MycG4 and shows the clear effect of the critical 3′-mutation on the drug binding interface. We performed a systematic analysis of the four available complex structures involving the same mutant MycG4, which can be considered a model system for parallel G4s, and revealed for the first time that the flexible flanking residues are recruited in a conserved and sequence-specific way, as well as unused potential for selective ligand-G4 hydrogen-bond interactions. Our results provide the true molecular basis for MycG4-targeting drugs and new critical insights into future rational design of drugs targeting MycG4 and parallel G4s that are prevalent in promoter and RNA G4s.
Original language | English (US) |
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Pages (from-to) | 5905-5915 |
Number of pages | 11 |
Journal | Nucleic acids research |
Volume | 49 |
Issue number | 10 |
DOIs | |
State | Published - Jun 4 2021 |
ASJC Scopus subject areas
- Genetics
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Dive into the research topics of 'Structural recognition of the MYC promoter G-quadruplex by a quinoline derivative: Insights into molecular targeting of parallel G-quadruplexes'. Together they form a unique fingerprint.Datasets
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Solution structure of the major MYC promoter G-quadruplex with a wild-type flanking sequence
Dickerhoff, J. (Contributor), Dai, J. (Contributor) & Yang, D. (Contributor), Protein Data Bank (PDB), Jun 23 2021
DOI: 10.2210/pdb7KBV/pdb, https://www.wwpdb.org/pdb?id=pdb_00007kbv
Dataset
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Solution structure of the major MYC promoter G-quadruplex in complex with NSC85697, a quinoline derivative
Dickerhoff, J. (Contributor), Dai, J. (Contributor) & Yang, D. (Contributor), Protein Data Bank (PDB), Jun 23 2021
DOI: 10.2210/pdb7KBX/pdb, https://www.wwpdb.org/pdb?id=pdb_00007kbx
Dataset
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Solution structure of the major MYC promoter G-quadruplex with a wild-type flanking in complex with NSC85697, a quinoline derivative
Dickerhoff, J. (Contributor), Dai, J. (Contributor) & Yang, D. (Contributor), Protein Data Bank (PDB), Jun 23 2021
DOI: 10.2210/pdb7KBW/pdb, https://www.wwpdb.org/pdb?id=pdb_00007kbw
Dataset