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Nucleic Acids Research 2005 33(14):4649-4659; doi:10.1093/nar/gki782
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Published online 16 August 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal

Jing Li, John J. Correia, Lei Wang1, John O. Trent1 and Jonathan B. Chaires1,*

Department of Biochemistry, University of Mississippi Medical Center 2500 North State Street, Jackson, MS 39216-4505, USA 1James Graham Brown Cancer Center, University of Louisville 529 South Jackson Street, Louisville, KY 40202, USA

*To whom correspondence should be addressed. Tel: +1 502 852 1172; Fax: +1 502 852 1153; Email: j.chaires{at}louisville.edu

Received July 22, 2005. Revised August 4, 2005. Accepted August 4, 2005.

The structure of human telomere DNA is of intense interest because of its role in the biology of both cancer and aging. The sequence [5'-AGGG(TTAGGG)3] has been used as a model for telomere DNA in both NMR and X-ray crystallographic studies, the results of which show dramatically different structures. In Na+ solution, NMR revealed an antiparallel G-quadruplex structure that featured both diagonal and lateral TTA loops. Crystallographic studies in the presence of K+ revealed a flattened, propeller-shaped structure featuring a parallel-stranded G-quadruplex with symmetrical external TTA loops. We report the results of biophysical experiments in solution and computational studies that are inconsistent with the reported crystal structure, indicating that a different structure exists in K+ solutions. Sedimentation coefficients were determined experimentally in both Na+ and K+ solutions and were compared with values calculated using bead models for the reported NMR and crystal structures. Although the solution NMR structure accurately predicted the observed S-value in Na+ solution, the crystal structure predicted an S-value that differed dramatically from that experimentally observed in K+ solution. The environments of loop adenines were probed by quantitative fluorescence studies using strategic and systematic single-substitutions of 2-aminopurine for adenine bases. Both fluorescence intensity and quenching experiments in K+ yielded results at odds with quantitative predictions from the reported crystal structure. Circular dichroism and fluorescence quenching studies in the presence of the crowding agent polyethylene glycol showed dramatic changes in the quadruplex structure in K+ solutions, but not in Na+ solutions, suggesting that the crystal environment may have selected for a particular conformational form. Molecular dynamics simulations were performed to yield model structures for the K+ quadruplex form that are consistent with our biophysical results and with previously reported chemical modification studies. These models suggest that the biologically relevant structure of the human telomere quadruplex in K+ solution is not the one determined in the published crystalline state.


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