Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter.
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.
Phan
Anh Tuân
AT
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. phantuan@mskcc.org
Kuryavyi
Vitaly
V
Gaw
Hai Yan
HY
Patel
Dinshaw J
DJ
D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054856:G-Quadruplexes; D016259:Genes, myc / Q000502:physiology*; D006147:Guanine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010751:Phosphopyruvate Hydratase / Q000235:genetics* / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D050436:Regulatory Elements, Transcriptional; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D011166:Porphyrins; D025521:Tumor Suppressor Proteins; C021096:tetra(4-N-methylpyridyl)porphine; D006147:Guanine; D004247:DNA; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase