Article

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

College of Pharmacy, The University of Arizona, 1703 E. Mabel Street, Tucson, AZ 85721, USA.
Nucleic Acids Research (Impact Factor: 9.11). 02/2006; 34(18):5133-44. DOI: 10.1093/nar/gkl610
Source: PubMed

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.

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