7WGW

NMR Solution Structure of a cGMP Fill-in Vacancy G-quadruplex Formed in the Oxidized BLM Gene Promoter

7WGW の概要

• エントリーDOI: 10.2210/pdb7wgw/pdb
• 分子名称: DNA (20-MER), CYCLIC GUANOSINE MONOPHOSPHATE (2 entities in total)
• 機能のキーワード: 8-oxo-7, 8-dihydroguanine, g-quadruplex, bloom syndrome protein, guanine metabolite, dna
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 6659.35

構造登録者

Wang, K.B.,Liu, Y.,Li, Y.,Li, J.,Dickerhoff, J.,Yang, M.H.,Yang, D.,Kong, L.Y. (登録日: 2021-12-29, 公開日: 2022-05-18, 最終更新日: 2024-05-15)

主引用文献

Wang, K.B.,Liu, Y.,Li, Y.,Dickerhoff, J.,Li, J.,Yang, M.H.,Yang, D.,Kong, L.Y.
Oxidative Damage Induces a Vacancy G-Quadruplex That Binds Guanine Metabolites: Solution Structure of a cGMP Fill-in Vacancy G-Quadruplex in the Oxidized BLM Gene Promoter.
J.Am.Chem.Soc., 144:6361-6372, 2022

PubMed Abstract: Guanine (G)-oxidation to 8-oxo-7,8-dihydroguanine (OG) by reactive oxygen species in genomic DNA has been implicated with various human diseases. G-quadruplex (G4)-forming sequences in gene promoters are highly susceptible to G-oxidation, which can subsequently cause gene activation. However, the underlying G4 structural changes that result from OG modifications remain poorly understood. Herein, we investigate the effect of G-oxidation on the gene promoter G4. For the first time, we show that OG can induce a G-vacancy-containing G4 (vG4), which can be filled in and stabilized by guanine metabolites and derivatives. We determined the NMR solution structure of the cGMP-fill-in oxidized promoter vG4. This is the first complex structure of an OG-induced vG4 from a human gene promoter sequence with a filled-in guanine metabolite. The high-resolution structure elucidates the structural features of the specific 5'-end cGMP-fill-in for the OG-induced vG4. Interestingly, the OG is removed from the G-core and becomes part of the 3'-end capping structure. A series of guanine metabolites and derivatives are evaluated for fill-in activity to the oxidation-induced vG4. Significantly, cellular guanine metabolites, such as cGMP and GTP, can bind and stabilize the OG-induced vG4, suggesting their potential regulatory role in response to oxidative damage in physiological and pathological processes. Our work thus provides exciting insights into how oxidative damage and cellular metabolites may work together through a G4-based epigenetic feature for gene regulation. Furthermore, the NMR structure can guide the rational design of small-molecule inhibitors that specifically target the oxidation-induced vG4s.

PubMed: 35352895
DOI: 10.1021/jacs.2c00435

実験手法

SOLUTION NMR