Solution structure of a thrombin binding aptamer complex with a non-planar platinum(ii) compound

Authors：Zhu, Bo-Chen; He, Juan; Xia, Xiao-Yu; Jiang, Jingxing; Liu, Wenting^*; Liu, Liu-Yi; Liang, Bing-Bing; Yao, Hua-Gang; Ke, Zhuofeng^*; Xia, Wei^*; Mao, Zong-Wan^*

Source：Chemical Science, 2022, 13(28): 8371-8379.

DOI：10.1039/d2sc01196d

• TELOMERIC G-QUADRUPLEX
• DNA
• RECOGNITION
• PROMOTER
• STABILITY
• MOLECULES
• SELECTION
• QUARTETS
• PARALLEL
• INSIGHTS

Thrombin Binding Aptamer (TBA) is a monomolecular well-defined two G-tetrad antiparallel G-quadruplex DNA that inhibits the activity of human alpha-thrombin. In this report, we synthesized a quasi-cross-shaped platinum(ii) compound (L ' 2LPt) with one cyclometalated and two carbene ligands. We found L ' 2LPt has selective affinity to bind the TBA G-quadruplex. A fibrinogen clotting assay revealed that L ' 2LPt can abrogate the inhibitory activity of TBA against thrombin. We solved the 1 : 1 L ' 2LPt-TBA complex structure by NMR, which revealed a unique self-adaptive property of L ' 2LPt upon binding to TBA. In the complex, a carbene ligand of L ' 2LPt rotates to pair with the cyclometalated ligand to form a plane stacking over half of the TBA G-tetrad and covered by lateral TT loops. It is notable that the heavy atom Pt stays out of the G-tetrad. Meanwhile, the other carbene ligand remains relatively perpendicular and forms a hydrogen bond with a guanine to anchor the L ' 2LPt position. This structure exhibits a quasi-cross-shaped Pt(ii) compound bound to the G-quadruplex with an unusual "wall-mounted" binding mode. Our structures provide insights into the specific recognition of antiparallel G-quadruplex DNA by a self-adaptive Pt(ii) compound and useful information for the design of selective G-quadruplex targeting non-planar molecules.

• Institution
  中山大学; 广东药学院