NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region.
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.
Dai
Jixun
J
College of Pharmacy, The University of Arizona, 1703 E. Mabel Street, Tucson, AZ 85721, USA.
Chen
Ding
D
Jones
Roger A
RA
Hurley
Laurence H
LH
Yang
Danzhou
D
D004247:DNA / Q000737:chemistry*; D004252:DNA Mutational Analysis; D054856:G-Quadruplexes; D019254:Genes, bcl-2; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D010758:Phosphorus / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011522:Protons; D012996:Solutions; D014158:Transcription, Genetic
D011522:Protons; D012996:Solutions; D010758:Phosphorus; D006147:Guanine; D004247:DNA