6LNZ

NMR solution structure of VEGF G-quadruplex bound a non-planar cyclometalated-carbene platinum(II) complex

Summary for 6LNZ

• Entry DOI: 10.2210/pdb6lnz/pdb
• Descriptor: DNA (5'-D(*CP*GP*GP*GP*GP*CP*GP*GP*GP*CP*CP*TP*TP*GP*GP*GP*CP*GP*GP*GP*GP*T)-3'), cyclometalated-carbene platinum(II) complex (2 entities in total)
• Functional Keywords: vegf g-quadruplex, solution structure, dna-ligand complex, platinum complex, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 7466.85

Authors

Liu, W.,Zhu, B.Z.,Mao, Z.W. (deposition date: 2020-01-02, release date: 2021-01-13, Last modification date: 2024-05-01)

Primary citation

Zhu, B.C.,He, J.,Liu, W.,Xia, X.Y.,Liu, L.Y.,Liang, B.B.,Yao, H.G.,Liu, B.,Ji, L.N.,Mao, Z.W.
Selectivity and Targeting of G-Quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics.
Angew.Chem.Int.Ed.Engl., 60:15340-15343, 2021

PubMed 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 -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 -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.

PubMed: 33899272
DOI: 10.1002/anie.202104624

Experimental method

SOLUTION NMR