Biophysical and X-ray structural studies of the (GGGTT)3GGG G-quadruplex in complex with N-methyl mesoporphyrin IX

Lin, Linda Yingqi; McCarthy, Sawyer; Powell, Barrett M.; Manurung, Yanti; Xiang, Irene M.; Dean, William L.; Chaires, Brad; Yatsunyk, Liliya A.; Ouellette, ed., Michel M.

doi:10.1371/journal.pone.0241513

Biophysical and X-ray structural studies of the (GGGTT)3GGG G-quadruplex in complex with N-methyl mesoporphyrin IX

Journal Article · Wed Nov 18 00:00:00 EST 2020 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0241513· OSTI ID:2325430

; ; Powell, Barrett M.; Manurung, Yanti; Xiang, Irene M.; Dean, William L.; Chaires, Brad; ; Ouellette, ed., Michel M.

The G-quadruplex (GQ) is a well-studied non-canonical DNA structure formed by G-rich sequences found at telomeres and gene promoters. Biological studies suggest that GQs may play roles in regulating gene expression, DNA replication, and DNA repair. Small molecule ligands were shown to alter GQ structure and stability and thereby serve as novel therapies, particularly against cancer. In this work, we investigate the interaction of a G-rich sequence, 5’-GGGTTGGGTTGGGTTGGG-3’ (T1), with a water-soluble porphyrin, N- methyl mesoporphyrin IX (NMM) via biophysical and X-ray crystallographic studies. UV-vis and fluorescence titrations, as well as a Job plot, revealed a 1:1 binding stoichiometry with an impressively tight binding constant of 30–50 μM ^-1 and ΔG ₂₉₈ of -10.3 kcal/mol. Eight extended variants of T1 (named T2 –T9) were fully characterized and T7 was identified as a suitable candidate for crystallographic studies. We solved the crystal structures of the T1- and T7-NMM complexes at 2.39 and 2.34 Å resolution, respectively. Both complexes form a 5’-5’ dimer of parallel GQs capped by NMM at the 3’ G-quartet, supporting the 1:1 binding stoichiometry. Our work provides invaluable details about GQ-ligand binding interactions and informs the design of novel anticancer drugs that selectively recognize specific GQs and modulate their stability for therapeutic purposes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2325430

Alternate ID(s):: OSTI ID: 1729713

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 11 Vol. 15; ISSN 1932-6203

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

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