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Nucleic Acids Res. 2006;34(18):5133-44. Epub 2006 Sep 22.

NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region.

Author information

1
College of Pharmacy, The University of Arizona, 1703 E. Mabel Street, Tucson, AZ 85721, USA.

Abstract

BCL2 protein functions as an inhibitor of cell apoptosis and has been found to be aberrantly expressed in a wide range of human diseases. A highly GC-rich region upstream of the P1 promoter plays an important role in the transcriptional regulation of BCL2. Here we report the NMR solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K+ solution. This well-defined mixed parallel/antiparallel-stranded G-quadruplex structure contains three G-tetrads of mixed G-arrangements, which are connected with two lateral loops and one side loop, and four grooves of different widths. The three loops interact with the core G-tetrads in a specific way that defines and stabilizes the overall G-quadruplex structure. The loop conformations are in accord with the experimental mutation and footprinting data. The first 3-nt loop adopts a lateral loop conformation and appears to determine the overall folding of the BCL2 G-quadruplex. The third 1-nt double-chain-reversal loop defines another example of a stable parallel-stranded structural motif using the G3NG3 sequence. Significantly, the distinct major BCL2 promoter G-quadruplex structure suggests that it can be specifically involved in gene modulation and can be an attractive target for pathway-specific drug design.

PMID:
16998187
PMCID:
PMC1636422
DOI:
10.1093/nar/gkl610
[Indexed for MEDLINE]
Free PMC Article

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