9UK8

Monomeric antiparallel G-quadruplex formed by d(G4C2)4

Summary for 9UK8

• Entry DOI: 10.2210/pdb9uk8/pdb
• Descriptor: DNA (5'-D(*GP*GP*GP*GP*CP*CP*GP*GP*GP*GP*CP*CP*GP*GP*GP*GP*CP*CP*GP*GP*GP*GP*CP*CP)-3'), POTASSIUM ION (3 entities in total)
• Functional Keywords: g-quadruplex, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 4
• Total formula weight: 30768.73

Authors

Geng, Y.,Cai, Q. (deposition date: 2025-04-17, release date: 2025-09-17)

Primary citation

Geng, Y.,Liu, C.,Miao, H.,Suen, M.C.,Xie, Y.,Zhang, B.,Han, W.,Wu, C.,Ren, H.,Chen, X.,Tai, H.C.,Wang, Z.,Zhu, G.,Cai, Q.
Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology. The high-resolution crystal structure of the parallel G4 reveals an eight-layered dimeric assembly, formed by two identical monomeric units. Each unit contains four stacked G-tetrads connected by three propeller CC loops and is stabilized through 5'-to-5' π-π interactions and coordination with a central K+ ion. Notably, the 3'-ending cytosines form a C·C+·C·C+ quadruple base pair stacking onto the adjacent G-tetrad layer. In contrast, the antiparallel G4 adopts a four-layered monomeric structure with three edgewise loops, where the C6 and C18 bases engage in stacking interaction with neighboring G-tetrad via a K+ ion. These structurally distinct G-quadruplexes provide mechanistic insights into C9orf72-associated neurodegeneration and offer potential targets for the development of structure-based therapeutic strategies for ALS and FTD.

PubMed: 40930530
DOI: 10.1093/nar/gkaf879

Experimental method

X-RAY DIFFRACTION (2.7 Å)