Structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat: Evidence for A-tetrad formation from NMR and molecular dynamics simulations

Evripidis Gavathiotis, Mark S. Searle

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

The structure of the intermolecular DNA quadruplex d(TTAGGGT)4, based on the human telomeric DNA sequence d(TTAGGG), has been determined in solution by NMR and restrained molecular dynamics simulations. The core GGG region forms a highly stable quadruplex with G-tetrads likely stabilised by K+ ions bound between tetrad plains. However, we have focused on the conformation of the adenines which differ considerably in base alignment, stability and dynamics from those in previously reported structures of d(AGGGT)4 and d(TAGGGT)4. We show unambiguously that the adenines of d(TTAGGGT)4 are involved in the formation of a relatively stable A-tetrad with well-defined glycosidic torsion angles (anti), hydrogen bonding network (adenine 6-NH2-adenine N1) defined by interbase NOEs, and base stacking interactions with the neighbouring G-tetrad. All of these structural features are apparent from NOE data involving both exchangeable and non-exchangeable protons. Thus, context-dependent effects appear to play some role in dictating preferred conformation, stability and dynamics. The structure of d(TTAGGGT)4 provides us with a model system for exploiting in the design of novel telomerase inhibitors that bind to and stabilise G-quadruplex structures.

Original languageEnglish (US)
Pages (from-to)1650-1656
Number of pages7
JournalOrganic and Biomolecular Chemistry
Volume1
Issue number10
DOIs
StatePublished - May 21 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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