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

An Erratum to this article was published on 01 September 2005

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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Figure 1: NMR study of the MYC promoter guanine-rich sequences.
Figure 2: Structure of the Pu24I quadruplex.
Figure 3: Interaction between the Pu24I quadruplex and different ligands as monitored by NMR.
Figure 4: NMR study of the Pu24I–TMPyP4 complex.
Figure 5: Six superposed refined structures of the Pu24I quadruplex–TMPyP4 complex.

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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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Correspondence to Anh Tuân Phan or Dinshaw J Patel.

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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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