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Nucleic Acids Research Advance Access originally published online on September 22, 2006
Nucleic Acids Research 2006 34(18):5133-5144; doi:10.1093/nar/gkl610
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Nucleic Acids Research, 2006, Vol. 34, No. 18 5133-5144
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

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

Jixun Dai1, Ding Chen1, Roger A. Jones2, Laurence H. Hurley1,3,4 and Danzhou Yang1,3,4,*

1 College of Pharmacy, The University of Arizona 1703 E. Mabel Street, Tucson, AZ 85721, USA 2 Department of Chemistry and Chemical Biology, Rutgers University 610 Taylor Road, Piscataway, NJ 08854, USA 3 Arizona Cancer Center 1515 N. Campbell Avenue, Tucson, AZ 85724, USA 4 BIO5 Institute, The University of Arizona 1140 E. South Campus Dr, Tucson, AZ 85721, USA

*To whom correspondence should be addressed: Tel: +1 520 626 5969; Fax: +1 520 626 6988; Email: yangd{at}pharmacy.arizona.edu

Received March 22, 2006. Revised August 3, 2006. Accepted August 3, 2006.

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.

Protein Data Bank accession no. PDB ID 2F8UBioMagResBank accession no. 6975


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