7X2Z

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

Summary for 7X2Z

• Entry DOI: 10.2210/pdb7x2z/pdb
• Descriptor: G-quadruplex DNA MYT1L, 4-(2-azanylethoxy)-N2,N6-bis[4-(2-pyrrolidin-1-ylethoxy)quinolin-2-yl]pyridine-2,6-dicarboxamide (2 entities in total)
• Functional Keywords: g-quadruplex, complex, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 9921.72

Authors

Liu, L.-Y.,Mao, Z.-W.,Liu, W. (deposition date: 2022-02-26, release date: 2022-06-08, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

SOLUTION NMR