DSSR-enabled G4 identification/annotation: PDB entry 7x3a
Summary information and primary citation
- PDB-id
- 7x3a
- Class
- DNA
- Method
- NMR
- Summary
- NMR solution structure of the 1:1 complex of a pyridostatin (pds) bound to a g-quadruplex myt1l
- Reference
- Liu L-Y, Ma TZ, Zeng YL, Liu W, Mao Z-W (2022): "Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes." J.Am.Chem.Soc., 144, 11878-11887. doi: 10.1021/jacs.2c04775.
- 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 (<i>e.g.</i>, 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 <i>via</i> hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N-H of PyPDS/PDS amide bonds interacts with two O<sub>6</sub>s of G-tetrad guanines <i>via</i> 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.
- G4 notes
- 3 G-tetrads, 1 G4 helix, 1 G4 stem, UDUU, hybrid3, 3+1, 3(-Lw-Ln-P)
Cartoon-block schematics in six views (download the tarball)
List of 3 G-tetrads
1 glyco-bond=s-ss sugar=-... groove=wn-- planarity=0.221 type=other O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27 2 glyco-bond=-s-- sugar=.-.. groove=wn-- planarity=0.100 type=planar O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28 3 glyco-bond=-s-- sugar=.-.. groove=wn-- planarity=0.137 type=planar O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29
List of 1 G4-helix
In DSSR, a G4-helix is defined by stacking interactions of G-tetrads, regardless of backbone connectivity, and may contain more than one G4-stem.
Helix#1, 3 G-tetrads, INTRA-molecular, with 1 stem
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1 glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27 2 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28 3 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29 step#1 mm(<>,outward) area=8.92 rise=3.81 twist=24.8 step#2 pm(>>,forward) area=13.85 rise=3.33 twist=26.0 strand#1 DNA glyco-bond=s-- sugar=-.. nts=3 GGG A.DG2,A.DG3,A.DG4 strand#2 DNA glyco-bond=-ss sugar=.-- nts=3 GGG A.DG20,A.DG19,A.DG18 strand#3 DNA glyco-bond=s-- sugar=... nts=3 GGG A.DG23,A.DG24,A.DG25 strand#4 DNA glyco-bond=s-- sugar=... nts=3 GGG A.DG27,A.DG28,A.DG29 |
| 2 stacking diagrams | |
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1 glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27 |
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2 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28 |
List of 1 G4-stem
In DSSR, a G4-stem is defined as a G4-helix with backbone connectivity. Bulges are also allowed along each of the four strands.
Stem#1, 3 G-tetrads, 3 loops, INTRA-molecular, UDUU, hybrid3, 3+1, 3(-Lw-Ln-P)
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1 glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27 2 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28 3 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29 step#1 mm(<>,outward) area=8.92 rise=3.81 twist=24.8 step#2 pm(>>,forward) area=13.85 rise=3.33 twist=26.0 strand#1 U DNA glyco-bond=s-- sugar=-.. nts=3 GGG A.DG2,A.DG3,A.DG4 strand#2 D DNA glyco-bond=-ss sugar=.-- nts=3 GGG A.DG20,A.DG19,A.DG18 strand#3 U DNA glyco-bond=s-- sugar=... nts=3 GGG A.DG23,A.DG24,A.DG25 strand#4 U DNA glyco-bond=s-- sugar=... nts=3 GGG A.DG27,A.DG28,A.DG29 loop#1 type=lateral strands=[#1,#2] nts=13 AGAGGAGAGCTCT A.DA5,A.DG6,A.DA7,A.DG8,A.DG9,A.DA10,A.DG11,A.DA12,A.DG13,A.DC14,A.DT15,A.DC16,A.DT17 loop#2 type=lateral strands=[#2,#3] nts=2 TT A.DT21,A.DT22 loop#3 type=propeller strands=[#3,#4] nts=1 T A.DT26 |