The crystal structure of an antiparallel chair-type G-quadruplex formed by Bromo-substituted human telomeric DNA

Abstract

Human telomeric guanine-rich DNA, which could adopt different G-quadruplex structures, plays important roles in protecting the cell from recombination and degradation. Although many of these structures were determined, the chair-type G-quadruplex structure remains elusive. Here, we present a crystal structure of the G-quadruplex composed of the human telomeric sequence d[GGGTTAGG 8 GTTAGGGTTAGG 20 G] with two dG to 8Br-dG substitutions at positions 8 and 20 with syn conformation in the K + solution. It forms a novel three-layer chair-type G-quadruplex with two linking trinucleotide loops. Particularly, T5 and T17 are coplanar with two water molecules stacking on the G-tetrad layer in a sandwich-like mode through a coordinating K + ion and an A6•A18 base pair. While a twisted Hoogsteen A12•T10 base pair caps on the top of G-tetrad core. The three linking TTA loops are edgewise and each DNA strand has two antiparallel adjacent strands. Our findings contribute to a deeper understanding and highlight the unique roles of loop and water molecule in the folding of the G-quadruplex.

Oxidative lesions modulate G-quadruplex stability and structure in the human BCL2 promoter

“…It is noteworthy that comparable G-quartets in bcl2ex and bcl2ex- oxo G19 differ in hydrogen bond directionalities, which suggests that the switch to the bcl2ex- oxo G19 structure would have to involve an unfolded or double helical intermediate. Interestingly, both bcl2ex and bcl2ex- oxo G19 exhibit capping structures flanking their G-quadruplex cores, which is in agreement with previously observed basket-type G-quadruplexes in solutions containing K + ions where extensive base pairing and stacking was found in the loops ( 54 , 55 ).…”

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…The alternative chair conformation contains three lateral loops. [12] A detailed examination of G4 polymorphism is beyond the scope of this article, but the interested reader is directed to many excellent reviews and studies on the topic. [7,11,[13][14][15][16][17] Clues to the existence of G4 were first uncovered during the 1970s and 1980s, when X-ray diffraction demonstrated the formation of helical structures from self-assembly of polyguanylic acid, [18,19] and Sen and Gilbert observed the self-association of G-rich DNA into four-stranded structures in monovalent salt buffer.…”

Beyond the double helix: DNA structural diversity and the PDB

“…Note the large A:G base-paired loop at the top of the structure. C , cartoon representation of the antiparallel chair arrangement formed by a human telomeric quadruplex ( 65 ), with three lateral loops. D , cartoon representation of the crystal structure of the c- MYC quadruplex ( 78 ).…”