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

2005; Nature Portfolio; Volume: 1; Issue: 3 Linguagem: Inglês

10.1038/nchembio723

1552-4469

Anh Tuân Phan, Vitaly Kuryavyi, Hai Yan Gaw, Dinshaw J. Patel,

RNA Interference and Gene Delivery

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.