Summary information and primary citation

PDB-id
8ijc
Class
DNA
Method
NMR
Summary
NMR solution structure of the 1:1 complex of a platinum(ii) ligand l1-transpt covalently bound to a g-quadruplex myt1l
Reference
Liu LY, Ma TZ, Zeng YL, Liu W, Zhang H, Mao ZW (2023): "Organic-Platinum Hybrids for Covalent Binding of G-Quadruplexes: Structural Basis and Application to Cancer Immunotherapy." Angew.Chem.Int.Ed.Engl., 62, e202305645. doi: 10.1002/anie.202305645.
Abstract
G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L<sub>1</sub> -cispt and L<sub>1</sub> -transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L<sub>1</sub> -transpt-MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L<sub>1</sub> -cispt- and L<sub>1</sub> -transpt-mediated genomic dysfunction could activate the retinoic acid-induced gene I (RIG-I) pathway and induce immunogenic cell death (ICD). The use of L<sub>1</sub> -cispt/L<sub>1</sub> -transpt-treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4-trageting drug design and their potential in immunotherapy.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, UDUU, hybrid3, 3+1, 3(-Lw-Ln-P)

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List of 3 G-tetrads

 1 glyco-bond=s-ss sugar=-.33 groove=wn-- planarity=0.245 type=bowl   O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2 glyco-bond=-s-- sugar=..3. groove=wn-- planarity=0.193 type=other  O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3 glyco-bond=-s-- sugar=3--. groove=wn-- planarity=0.294 type=bowl   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
 1  glyco-bond=s-ss sugar=-.33 groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2  glyco-bond=-s-- sugar=..3. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3  glyco-bond=-s-- sugar=3--. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29
  step#1  mm(<>,outward)  area=9.58  rise=3.55 twist=22.7
  step#2  pm(>>,forward)  area=14.34 rise=3.87 twist=20.3
  strand#1 DNA glyco-bond=s-- sugar=-.3 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=33- nts=3 GGG A.DG23,A.DG24,A.DG25
  strand#4 DNA glyco-bond=s-- sugar=3.. nts=3 GGG A.DG27,A.DG28,A.DG29

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2 stacking diagrams 
 1  glyco-bond=s-ss sugar=-.33 groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2  glyco-bond=-s-- sugar=..3. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
  step#1  mm(<>,outward)  area=9.58  rise=3.55 twist=22.7

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 2  glyco-bond=-s-- sugar=..3. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3  glyco-bond=-s-- sugar=3--. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29
  step#2  pm(>>,forward)  area=14.34 rise=3.87 twist=20.3

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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-tetrads, 3 loops, INTRA-molecular, UDUU, hybrid3, 3+1, 3(-Lw-Ln-P)
 1  glyco-bond=s-ss sugar=-.33 groove=wn-- Major-->WC O- nts=4 GGGG A.DG2,A.DG20,A.DG23,A.DG27
 2  glyco-bond=-s-- sugar=..3. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG3,A.DG19,A.DG24,A.DG28
 3  glyco-bond=-s-- sugar=3--. groove=wn-- WC-->Major O+ nts=4 GGGG A.DG4,A.DG18,A.DG25,A.DG29
  step#1  mm(<>,outward)  area=9.58  rise=3.55 twist=22.7
  step#2  pm(>>,forward)  area=14.34 rise=3.87 twist=20.3
  strand#1  U DNA glyco-bond=s-- sugar=-.3 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=33- nts=3 GGG A.DG23,A.DG24,A.DG25
  strand#4  U DNA glyco-bond=s-- sugar=3.. 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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