Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biochemistry

Background:

• DNA G-quadruplexes are crucial in cancer therapeutics and supramolecular assembly.
• Telomeric G-quadruplexes (Tel26) are key targets for inhibiting telomerase activity.

Purpose of the Study:

• To investigate the binding of a platinum(II)-based tripod (Pt-tripod) to the hybrid-1 human telomeric G-quadruplex (Tel26).
• To elucidate the structural basis of Pt-tripod-Tel26 interactions and their effect on telomerase activity.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy to solve complex structures.
• Biochemical assays to assess telomerase inhibition.

Main Results:

• Pt-tripod specifically binds Tel26, inhibiting telomerase activity.
• NMR structures reveal 1:1 and unique 4:2 dimeric Pt-tripod-Tel26 complexes.
• Binding occurs at the 5'-end at low ratios and the 3'-end at higher ratios, forming an interlocked dimeric structure.

Conclusions:

• The study provides structural insights into small molecule binding dynamics with G-quadruplexes.
• Findings advance understanding of DNA damage mechanisms and higher-order G-quadruplex assembly.
• Pt-tripod represents a promising agent for cancer therapeutics targeting telomerase.