Detailed DSSR results for the G-quadruplex: PDB entry 7png

PDB id

7png

Class

DNA

Method

NMR

Summary

Solution structure of 1:1 complex of an indoloquinoline derivative syuiq-5 to parallel quadruplex-duplex (q-d) hybrid

Reference

Vianney YM, Weisz K (2021): "Indoloquinoline Ligands Favor Intercalation at Quadruplex-Duplex Interfaces." Chemistry, e202103718. doi: 10.1002/chem.202103718.

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 7 M -1 and large exothermicities Δ H ° 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 N 5-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.

G4 notes

3 G-tetrads, 1 G4 helix, 1 G4 stem, 2(-P-P-P), parallel(4+0), UUUU

 1 glyco-bond=---- sugar=--.- groove=---- planarity=0.261 type=other  nts=4 GGGG A.DG4,A.DG7,A.DG12,A.DG16
 2 glyco-bond=---- sugar=---- groove=---- planarity=0.235 type=other  nts=4 GGGG A.DG5,A.DG8,A.DG13,A.DG17
 3 glyco-bond=---s sugar=---- groove=--wn planarity=0.316 type=other  nts=4 GGGG A.DG9,A.DG14,A.DG18,A.DG36

Helix#1, 3 G-tetrad layers, INTRA-molecular, with 1 stem

	1 glyco-bond=---- sugar=--.- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG7,A.DG12,A.DG16 2 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG8,A.DG13,A.DG17 3 glyco-bond=s--- sugar=---- groove=n--w WC-->Major nts=4 GGGG A.DG36,A.DG9,A.DG14,A.DG18 step#1 pm(>>,forward) area=10.64 rise=3.42 twist=28.8 step#2 pm(>>,forward) area=11.65 rise=3.48 twist=27.4 strand#1 DNA glyco-bond=--s sugar=--- nts=3 GGG A.DG4,A.DG5,A.DG36 strand#2 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG7,A.DG8,A.DG9 strand#3 DNA glyco-bond=--- sugar=.-- nts=3 GGG A.DG12,A.DG13,A.DG14 strand#4 DNA glyco-bond=--- sugar=--- nts=3 GGG A.DG16,A.DG17,A.DG18 Download PDB file Interactive view in 3Dmol.js
2 stacking diagrams
	1 glyco-bond=---- sugar=--.- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG7,A.DG12,A.DG16 2 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG8,A.DG13,A.DG17 step#1 pm(>>,forward) area=10.64 rise=3.42 twist=28.8 Download PDB file Interactive view in 3Dmol.js
	2 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG8,A.DG13,A.DG17 3 glyco-bond=s--- sugar=---- groove=n--w WC-->Major nts=4 GGGG A.DG36,A.DG9,A.DG14,A.DG18 step#2 pm(>>,forward) area=11.65 rise=3.48 twist=27.4 Download PDB file Interactive view in 3Dmol.js

Stem#1, 2 G-tetrad layers, 3 loops, INTRA-molecular, UUUU, parallel, 2(-P-P-P), parallel(4+0)

1 glyco-bond=---- sugar=--.- groove=---- WC-->Major nts=4 GGGG A.DG4,A.DG7,A.DG12,A.DG16 2 glyco-bond=---- sugar=---- groove=---- WC-->Major nts=4 GGGG A.DG5,A.DG8,A.DG13,A.DG17 step#1 pm(>>,forward) area=10.64 rise=3.42 twist=28.8 strand#1 U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG4,A.DG5 strand#2 U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG7,A.DG8 strand#3 U DNA glyco-bond=-- sugar=.- nts=2 GG A.DG12,A.DG13 strand#4 U DNA glyco-bond=-- sugar=-- nts=2 GG A.DG16,A.DG17 loop#1 type=propeller strands=[#1,#2] nts=1 T A.DT6 loop#2 type=propeller strands=[#2,#3] nts=3 GTA A.DG9,A.DT10,A.DA11 loop#3 type=propeller strands=[#3,#4] nts=2 GT A.DG14,A.DT15 Download PDB file Interactive view in 3Dmol.js

 1 type=lateral   helix=#1 nts=19 GCTAGTCATTTTGACTAGG A.DG18,A.DC19,A.DT20,A.DA21,A.DG22,A.DT23,A.DC24,A.DA25,A.DT26,A.DT27,A.DT28,A.DT29,A.DG30,A.DA31,A.DC32,A.DT33,A.DA34,A.DG35,A.DG36