Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter

Nat Chem Biol. 2005 Aug;1(3):167-73. doi: 10.1038/nchembio723. Epub 2005 Jul 17.


It has been widely accepted that DNA can adopt other biologically relevant structures beside the Watson-Crick double helix. One recent important example is the guanine-quadruplex (G-quadruplex) structure formed by guanine tracts found in the MYC (or c-myc) promoter region, which regulates the transcription of the MYC oncogene. Stabilization of this G-quadruplex by ligands, such as the cationic porphyrin TMPyP4, decreases the transcriptional level of MYC. Here, we report the first structure of a DNA fragment containing five guanine tracts from this region. An unusual G-quadruplex fold, which was derived from NMR restraints using unambiguous model-independent resonance assignment approaches, involves a core of three stacked guanine tetrads formed by four parallel guanine tracts with all anti guanines and a snapback 3'-end syn guanine. We have determined the structure of the complex formed between this G-quadruplex and TMPyP4. This structural information, combined with details of small-molecule interaction, provides a platform for the design of anticancer drugs targeting multi-guanine-tract sequences that are found in the MYC and other oncogenic promoters, as well as in telomeres.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • DNA / chemistry*
  • DNA / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • G-Quadruplexes
  • Genes, myc / physiology*
  • Guanine / chemistry*
  • Guanine / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Phosphopyruvate Hydratase / genetics*
  • Phosphopyruvate Hydratase / metabolism
  • Porphyrins / chemistry*
  • Porphyrins / metabolism
  • Promoter Regions, Genetic*
  • Protein Folding
  • Regulatory Elements, Transcriptional
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Porphyrins
  • Tumor Suppressor Proteins
  • tetra(4-N-methylpyridyl)porphine
  • Guanine
  • DNA
  • ENO1 protein, human
  • Phosphopyruvate Hydratase

Associated data

  • PDB/2A5P
  • PDB/2A5R
  • PubChem-Substance/866159
  • PubChem-Substance/866160
  • PubChem-Substance/866161
  • PubChem-Substance/866162