Nucleic Acids Research Advance Access originally published online on August 24, 2007
Nucleic Acids Research 2007 35(17):5799-5808; doi:10.1093/nar/gkm609
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Nucleic Acids Research, 2007, Vol. 35, No. 17 5799-5808
© 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 |
Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter
Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK
*To whom correspondence should be addressed. Tel: +44 207 753 5969; Fax: +44 207 753 5970; Email: sephen.neidle{at}pharmacy.ac.uk
Received May 18, 2007. Revised July 24, 2007. Accepted July 26, 2007.
The 22-nt c-kit87 promoter sequence is unique within the human genome. Its fold and tertiary structure have recently been determined by NMR methods [Phan,A.T., Kuryavyi,V., Burge,S., Neidle,S. and Patel,D.J. (2007) Structure of an unprecedented G-quadruplex scaffold in the c-kit promoter. J. Am. Chem. Soc., 129, 4386–4392], and does not have precedent among known DNA quadruplexes. We show here using bioinformatics and molecular dynamics simulations methods that (i) none of the closely related sequences (encompassing all nucleotides not involved in the maintenance of structural integrity) occur immediately upstream (<100 nt) of a transcription start site, and (ii) that all of these sequences correspond to the same stable tertiary structure. It is concluded that the c-kit87 tertiary structure may also be formed in a very small number of other loci in the human genome, but the likelihood of these playing a significant role in the expression of particular genes is very low. The c-kit87 quadruplex thus fulfils a fundamental criterion of a ‘good’ drug target, in that it possesses distinctive three-dimensional structural features that are only present in at most a handful of other genes.
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