6SX3

Intercalation of heterocyclic ligand between quartets in G-rich tetrahelical structure

Summary for 6SX3

• Entry DOI: 10.2210/pdb6sx3/pdb
• NMR Information: BMRB: 34435
• Descriptor: VK2, ~{N}2,~{N}6-bis(1-methylquinolin-1-ium-3-yl)pyridine-2,6-dicarboxamide (2 entities in total)
• Functional Keywords: intercalation agcga-quadruplex g-quadruplex heterocyclic ligand, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 10337.84

Authors

Kotar, A.,Kocman, V.,Plavec, J. (deposition date: 2019-09-24, release date: 2019-12-11, Last modification date: 2024-05-15)

Primary citation

Kotar, A.,Kocman, V.,Plavec, J.
Intercalation of a Heterocyclic Ligand between Quartets in a G-Rich Tetrahelical Structure.
Chemistry, 26:814-817, 2020

PubMed Abstract: YES G-rich oligonucleotide VK2 folds into an AGCGA-quadruplex tetrahelical structure distinct and significantly different from G-quadruplexes, even though it contains four G tracts. Herein, a bis-quinolinium ligand 360A with high affinity for G-quadruplex structures and selective telomerase inhibition is shown to strongly bind to VK2. Upon binding, 360A does not induce a conformational switch from VK2 to an expected G-quadruplex. In contrast, NMR structural study revealed formation of a well-defined VK2-360A complex with a 1:1 binding stoichiometry, in which 360A intercalates between GAGA- and GCGC-quartets in the central cavity of VK2. This is the first high-resolution structure of a G-quadruplex ligand intercalating into a G-rich tetrahelical fold. This unique mode of ligand binding into tetrahelical DNA architecture offers insights into the stabilization of an AGCGA-quadruplex by a heterocyclic ligand and provides guidelines for rational design of novel VK2 binding molecules with selectivity for different DNA secondary structures.

PubMed: 31750579
DOI: 10.1002/chem.201904923

Experimental method

SOLUTION NMR