7X3A

NMR solution structure of the 1:1 complex of a pyridostatin (PDS) bound to a G-quadruplex MYT1L

7X3A の概要

• エントリーDOI: 10.2210/pdb7x3a/pdb
• 分子名称: G-quadruplex DNA MYT1L, 4-(2-azanylethoxy)-N2,N6-bis[4-(2-azanylethoxy)quinolin-2-yl]pyridine-2,6-dicarboxamide (2 entities in total)
• 機能のキーワード: g-quadruplex, complex, dna
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 9813.54

構造登録者

Liu, L.-Y.,Mao, Z.-W.,Liu, W. (登録日: 2022-02-28, 公開日: 2022-06-08, 最終更新日: 2024-05-15)

主引用文献

Liu, L.-Y.,Ma, T.Z.,Zeng, Y.L.,Liu, W.,Mao, Z.-W.
Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes.
J.Am.Chem.Soc., 144:11878-11887, 2022

PubMed Abstract: The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (, PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex-duplex hybrid. The structures indicate that the rigid aromatic rings of PyPDS/PDS linked by flexible amide bonds match adaptively with G-tetrad planes, enhancing π-π stacking and achieving specific recognition of G4s. The aliphatic amine side chains of PyPDS/PDS adjust conformation to interact with the phosphate backbone hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N-H of PyPDS/PDS amide bonds interacts with two Os of G-tetrad guanines hydrogen bonding, achieving a further increase in affinity for G4s, which is different from most G4 ligands. Our findings reveal from structural perspectives that the rational assembly of rigid and flexible structural units in a ligand can synergistically improve the selectivity and affinity for G4s through spatial selective and adaptive matching.

PubMed: 35749293
DOI: 10.1021/jacs.2c04775

実験手法

SOLUTION NMR