Summary information

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 (e.g., 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 via hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N-H of PyPDS/PDS amide bonds interacts with two O6s of G-tetrad guanines via 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, 3(-Lw-Ln-P), hybrid-2(3+1), UDUU

Base-block schematics in six views

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List of 3 G-tetrads

 1 glyco-bond=s-ss sugar=-... groove=wn-- planarity=0.221 type=other  nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2 glyco-bond=-s-- sugar=.-.. groove=wn-- planarity=0.100 type=planar nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3 glyco-bond=-s-- sugar=.-.. groove=wn-- planarity=0.137 type=planar 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-tetrad layers, INTRA-molecular, with 1 stem

 1  glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2  glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3  glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major 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

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2 stacking diagrams
 1  glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
2 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
step#1 mm(<>,outward) area=8.92 rise=3.81 twist=24.8

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 2  glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
3 glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29
step#2 pm(>>,forward) area=13.85 rise=3.33 twist=26.0

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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-tetrad layers, 3 loops, INTRA-molecular, UDUU, hybrid-(mixed), 3(-Lw-Ln-P), hybrid-2(3+1)

 1  glyco-bond=s-ss sugar=-... groove=wn-- Major-->WC nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2  glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3  glyco-bond=-s-- sugar=.-.. groove=wn-- WC-->Major 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

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