Crystal Structure Analysis Of The Non-Canonical G-Rich DNA TET25 In Complex With PyDH2 As A Potential Anticancer Therapeutic

Document Type

Poster Session

Publication Date

2-8-2024

Published In

Biophysical Journal

Abstract

Guanine quadruplexes (GQs) are non-canonical secondary DNA structures comprised of stabilized stacks of guanine tetrads (G-tetrad). GQs are involved in various biological processes and have been implicated in human diseases, notably cancer. Small molecule ligands can change the folding and stability of GQs. The ability of ligands to control the structure of GQs can be used to develop therapeutic treatments. Here, we analyze the crystal structure of telomeric DNA from Tetrahymena thermophila (TET25) in complex with the highly selective GQ ligand PyDH2. Structural and spectroscopic data indicate that TET25 alone adopts a mixture of three GQ conformations, the major of which is a hybrid four G-tetrad GQ. In the presence of PyDH2, TET25 refolds into an antiparallel GQ conformation. The TET25-PyDH2 antiparallel structure was crystallized and successfully solved using molecular replacement. The crystal structure revealed that PyDH2 intercalates between the second and third G-tetrads of the antiparallel conformation. This intercalation is unique and has only been observed for the second time. Typically, ligands interact with GQs via end-stacking with the terminal G-tetrad. This study has increased our understanding of how small molecule ligands interact and affect the structure of GQ, allowing for the design of more effective GQ binders.

Conference

Biophysical Society Annual Meeting 2024

Conference Dates

February 10-14, 2024

Conference Location

Philadelphia, PA

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