7KBX

Solution structure of the major MYC promoter G-quadruplex in complex with NSC85697, a quinoline derivative

Summary for 7KBX

• Entry DOI: 10.2210/pdb7kbx/pdb
• Related: 1XAV 7KBV 7KBW
• NMR Information: BMRB: 30805
• Descriptor: Myc2345_T23, 2-[(~{E})-2-(3-methoxy-4-oxidanyl-phenyl)ethenyl]-1-methyl-quinoline-4-carboxamide (2 entities in total)
• Functional Keywords: g-quadruplex dna, drug-dna complex, dna
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 7679.26

Authors

Dickerhoff, J.,Yang, D. (deposition date: 2020-10-03, release date: 2021-06-23, Last modification date: 2024-05-01)

Primary citation

Dickerhoff, J.,Dai, J.,Yang, D.
Structural recognition of the MYC promoter G-quadruplex by a quinoline derivative: insights into molecular targeting of parallel G-quadruplexes.
Nucleic Acids Res., 49:5905-5915, 2021

PubMed 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.

PubMed: 33978746
DOI: 10.1093/nar/gkab330

Experimental method

SOLUTION NMR