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Nucleic Acids Research Advance Access originally published online on July 10, 2007
Nucleic Acids Research 2007 35(15):4927-4940; doi:10.1093/nar/gkm522
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Nucleic Acids Research, 2007, Vol. 35, No. 15 4927-4940
© 2007 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

Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence

Jixun Dai1, Megan Carver1, Chandanamali Punchihewa1, Roger A. Jones2 and Danzhou Yang1,3,4,*

1College of Pharmacy, The University of Arizona, 1703 E. Mabel St, Tucson, AZ 85721, 2Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, 3Arizona Cancer Center, 1515 N. Campbell Avenue, Tucson, AZ 85724 and 4BIO5 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 May 28, 2007. Revised June 19, 2007. Accepted June 21, 2007.

Formation of the G-quadruplex in the human telomeric sequence can inhibit the activity of telomerase, thus the intramolecular telomeric G-quadruplexes have been considered as an attractive anticancer target. Information of intramolecular telomeric G-quadruplex structures formed under physiological conditions is important for structure-based drug design. Here, we report the first structure of the major intramolecular G-quadruplex formed in a native, non-modified human telomeric sequence in K+ solution. This is a hybrid-type mixed parallel/antiparallel-G-stranded G-quadruplex, one end of which is covered by a novel T:A:T triple capping structure. This structure (Hybrid-2) and the previously reported Hybrid-1 structure differ in their loop arrangements, strand orientations and capping structures. The distinct capping structures appear to be crucial for the favored formation of the specific hybrid-type intramolecular telomeric G-quadruplexes, and may provide specific binding sites for drug targeting. Our study also shows that while the hybrid-type G-quadruplexes appear to be the major conformations in K+ solution, human telomeric sequences are always in equilibrium between Hybrid-1 and Hybrid-2 structures, which is largely determined by the 3'-flanking sequence. Furthermore, both hybrid-type G-quadruplexes suggest a straightforward means for multimer formation with effective packing in the human telomeric sequence and provide important implications for drug targeting of G-quadruplexes in human telomeres.


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