Summary information and primary citation

PDB-id
6lnz
Class
DNA
Method
NMR
Summary
NMR solution structure of vegf g-quadruplex bound a non-planar cyclometalated-carbene platinum(ii) complex
Reference
Zhu BC, He J, Liu W, Xia XY, Liu LY, Liang BB, Yao HG, Liu B, Ji LN, Mao ZW (2021): "Selectivity and Targeting of G-Quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics." Angew.Chem.Int.Ed.Engl., 60, 15340-15343. doi: 10.1002/anie.202104624.
Abstract
G-quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4-DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF-G4 (a promoter G4) shows that Pt1 matches 3'-G-tetrad of VEGF-G4 through Cl<sub>-</sub> -dissociation and loop rearrangement of VEGF-G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate-determining binding step, Cl<sub>-</sub> -dissociation upon G4-binding, is 2-3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4-binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
G4 notes
3 G-tetrads, 1 G4 helix, 1 G4 stem, UUUU, parallel, 4+0, 3(-P-P-P)

Cartoon-block schematics in six views (download the tarball)

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List of 3 G-tetrads

 1 glyco-bond=---- sugar=3-.. groove=---- planarity=0.139 type=planar O+ nts=4 GGGG A.DG3,A.DG7,A.DG14,A.DG18
 2 glyco-bond=---- sugar=3... groove=---- planarity=0.091 type=planar O+ nts=4 GGGG A.DG4,A.DG8,A.DG15,A.DG19
 3 glyco-bond=---- sugar=-3-3 groove=---- planarity=0.116 type=planar O+ nts=4 GGGG A.DG5,A.DG9,A.DG16,A.DG20

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=---- sugar=3-.. groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG7,A.DG14,A.DG18
 2  glyco-bond=---- sugar=3... groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG15,A.DG19
 3  glyco-bond=---- sugar=-3-3 groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG16,A.DG20
  step#1  pm(>>,forward)  area=16.65 rise=3.77 twist=25.3
  step#2  pm(>>,forward)  area=12.12 rise=3.75 twist=27.6
  strand#1 DNA glyco-bond=--- sugar=33- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2 DNA glyco-bond=--- sugar=-.3 nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#3 DNA glyco-bond=--- sugar=..- nts=3 GGG A.DG14,A.DG15,A.DG16
  strand#4 DNA glyco-bond=--- sugar=..3 nts=3 GGG A.DG18,A.DG19,A.DG20

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2 stacking diagrams 
 1  glyco-bond=---- sugar=3-.. groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG7,A.DG14,A.DG18
 2  glyco-bond=---- sugar=3... groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG15,A.DG19
  step#1  pm(>>,forward)  area=16.65 rise=3.77 twist=25.3

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 2  glyco-bond=---- sugar=3... groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG15,A.DG19
 3  glyco-bond=---- sugar=-3-3 groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG16,A.DG20
  step#2  pm(>>,forward)  area=12.12 rise=3.75 twist=27.6

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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, UUUU, parallel, 4+0, 3(-P-P-P)
 1  glyco-bond=---- sugar=3-.. groove=---- WC-->Major O+ nts=4 GGGG A.DG3,A.DG7,A.DG14,A.DG18
 2  glyco-bond=---- sugar=3... groove=---- WC-->Major O+ nts=4 GGGG A.DG4,A.DG8,A.DG15,A.DG19
 3  glyco-bond=---- sugar=-3-3 groove=---- WC-->Major O+ nts=4 GGGG A.DG5,A.DG9,A.DG16,A.DG20
  step#1  pm(>>,forward)  area=16.65 rise=3.77 twist=25.3
  step#2  pm(>>,forward)  area=12.12 rise=3.75 twist=27.6
  strand#1  U DNA glyco-bond=--- sugar=33- nts=3 GGG A.DG3,A.DG4,A.DG5
  strand#2  U DNA glyco-bond=--- sugar=-.3 nts=3 GGG A.DG7,A.DG8,A.DG9
  strand#3  U DNA glyco-bond=--- sugar=..- nts=3 GGG A.DG14,A.DG15,A.DG16
  strand#4  U DNA glyco-bond=--- sugar=..3 nts=3 GGG A.DG18,A.DG19,A.DG20
  loop#1 type=propeller strands=[#1,#2] nts=1 C A.DC6
  loop#2 type=propeller strands=[#2,#3] nts=4 CCTT A.DC10,A.DC11,A.DT12,A.DT13
  loop#3 type=propeller strands=[#3,#4] nts=1 C A.DC17

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