Abstract
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.
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Acknowledgements
We thank Y. Modi for his participation at the early stage of this study. H.Y.G. is a student from the Bioinformatics Workshop at the City College of New York supported by a grant from Howard Hughes Medical Institute for undergraduate science education. D.J.P. is a member of the New York Structural Biology Center supported by US National Institutes of Health grant GM66354. This research was supported by US National Institutes of Health grant GM34504.
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Supplementary information
Supplementary Fig. 1
NMR spectral assignment for Pu24I. (PDF 391 kb)
Supplementary Fig. 2
Folding topology of Pu24I. (PDF 329 kb)
Supplementary Fig. 3
Base stacking overlap patterns between adjacent G-tetrad planes in a representative intensity-refined structure of the Pu24I quadruplex. (PDF 7209 kb)
Supplementary Fig. 4
Loops in the Pu24I quadruplex. (PDF 1128 kb)
Supplementary Fig. 5
NMR spectra of Pu24I and modified sequences. (PDF 263 kb)
Supplementary Fig. 6
Comparison between the structures of Pu24I and Pu25I. (PDF 777 kb)
Supplementary Fig. 7
NMR study of the Pu24I quadruplex-TMPyP4 complex. (PDF 649 kb)
Supplementary Table 1
Statistics of the computed structures. (PDF 116 kb)
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Phan, A., Kuryavyi, V., Gaw, H. et al. Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter. Nat Chem Biol 1, 167–173 (2005). https://doi.org/10.1038/nchembio723
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DOI: https://doi.org/10.1038/nchembio723
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