Solution Structure of a Thrombin Binding Aptamer Complex with a Non-planar Platinum(ii) Compound

Thrombin Binding Aptamer (TBA) is a monomolecular well-defined two G-tetrad antiparallel G-quadruplex DNA that inhibits the activity of human α-thrombin. In this report, we synthesized a quasi-cross-shaped platinum(ii) compound (L'LPt) with one cyclometalated and two carbene ligands. We found L'LPt has selective affinity to bind the TBA G-quadruplex. A fibrinogen clotting assay revealed that L'LPt can abrogate the inhibitory activity of TBA against thrombin. We solved the 1 : 1 L'LPt-TBA complex structure by NMR, which revealed a unique self-adaptive property of L'LPt upon binding to TBA. In the complex, a carbene ligand of L'LPt 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'LPt 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.