7KBW

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

7KBW の概要

• エントリーDOI: 10.2210/pdb7kbw/pdb
• 関連するPDBエントリー: 7KBV
• NMR情報: BMRB: 30804
• 分子名称: Myc2345, 2-[(~{E})-2-(3-methoxy-4-oxidanyl-phenyl)ethenyl]-1-methyl-quinoline-4-carboxamide (2 entities in total)
• 機能のキーワード: g-quadruplex dna, drug-dna complex, dna
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7704.27

構造登録者

Dickerhoff, J.,Yang, D. (登録日: 2020-10-03, 公開日: 2021-06-23, 最終更新日: 2024-05-01)

主引用文献

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

実験手法

SOLUTION NMR