7PNE

Parallel Q-D hybrid with 3' duplex stem-loop as a lateral snapback loop

Summary for 7PNE

• Entry DOI: 10.2210/pdb7pne/pdb
• NMR Information: BMRB: 34664
• Descriptor: TTAMycdup-3sbl (1 entity in total)
• Functional Keywords: g-quadruplex, duplex, quadruplex-duplex junction, dna
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 11210.25

Authors

Vianney, Y.M.,Weisz, K. (deposition date: 2021-09-06, release date: 2021-12-29, Last modification date: 2024-06-19)

Primary citation

Vianney, Y.M.,Weisz, K.
Indoloquinoline Ligands Favor Intercalation at Quadruplex-Duplex Interfaces.
Chemistry, 28:e202103718-e202103718, 2022

PubMed Abstract: Quadruplex-duplex (Q-D) junctions are increasingly considered promising targets for medicinal and technological applications. Here, a Q-D hybrid with a hairpin-type snapback loop coaxially stacked onto the quadruplex 3'-outer tetrad was designed and employed as a target structure for the indoloquinoline ligand SYUIQ-5. NMR spectral analysis demonstrated high-affinity binding of the ligand at the quadruplex-duplex interface with association constants determined by isothermal titration calorimetry of about 10  M and large exothermicities ΔH° of -14 kcal/mol in a 120 mM K buffer at 40 °C. Determination of the ligand-bound hybrid structure revealed intercalation of SYUIQ-5 between 3'-outer tetrad and the neighboring CG base pair, maximizing π-π stacking as well as electrostatic interactions with guanine carbonyl groups in close vicinity to the positively charged protonated quinoline nitrogen of the tetracyclic indoloquinoline. Exhibiting considerable flexibility, the SYUIQ-5 sidechain resides in the duplex minor groove. Based on comparative binding studies with the non-substituted N5-methylated indoloquinoline cryptolepine, the sidechain is suggested to confer additional affinity and to fix the alignment of the intercalated indoloquinoline aromatic core. However, selectivity for the Q-D junction mostly relies on the geometry and charge distribution of the indoloquinoline ring system. The presented results are expected to provide valuable guidelines for the design of ligands specifically targeting Q-D interfaces.

PubMed: 34905232
DOI: 10.1002/chem.202103718

Experimental method

SOLUTION NMR