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Recognition of the four Watson-Crick base pairs in the DNA minor groove by synthetic ligands

White, Sarah and Szewczyk, Jason W. and Turner, James M. and Baird, Eldon E. and Dervan, Peter B. (1998) Recognition of the four Watson-Crick base pairs in the DNA minor groove by synthetic ligands. Nature, 391 (6666). pp. 468-471. ISSN 0028-0836. http://resolver.caltech.edu/CaltechAUTHORS:20150609-092314492

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Abstract

The design of synthetic ligands that read the information stored in the DNA double helix has been a long-standing goal at the interface of chemistry and biology. Cell-permeable small molecules that target predetermined DNA sequences offer a potential approach for the regulation of gene expression. Oligodeoxynucleotides that recognize the major groove of double-helical DNA via triple-helix formation bind to a broad range of sequences with high affinity and specificity. Although oligonucleotides and their analogues have been shown to interfere with gene expression, the triple-helix approach is limited to recognition of purines and suffers from poor cellular uptake. The subsequent development of pairing rules for minor-groove binding polyamides containing pyrrole (Py) and imidazole (Im) amino acids offers a second code to control sequence specificity. An Im/Py pair distinguishes G C from C G and both of these from A T/T A base pairs. A Py/Py pair specifies A,T from G,C but does not distinguish A T from T A. To break this degeneracy, we have added a new aromatic amino acid, 3-hydroxypyrrole (Hp), to the repertoire to test for pairings that discriminate A T from T A. We find that replacement of a single hydrogen atom with a hydroxy group in a Hp/Py pairing regulates affinity and specificity by an order of magnitude. By incorporation of this third amino acid, hydroxypyrrole–imidazole–pyrrole polyamides form four ring-pairings (Im/Py, Py/Im, Hp/Py and Py/Hp) which distinguish all four Watson–Crick base pairs in the minor groove of DNA.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/35106DOIArticle
http://www.nature.com/nature/journal/v391/n6666/full/391468a0.htmlPublisherArticle
http://www.nature.com/nature/journal/v391/n6666/suppinfo/391468a0.htmlPublisherSupplementary Information
Additional Information:© 1998 Macmillan Publishers Ltd. Received 29 September; accepted 24 November 1997. We are grateful to the NIH for research support and National Research service Awards to S.W. and J.W.S., to the NSF for a predoctorial fellowship to S.W., to J. Edward Richter for an undergraduate fellowship to J.M.T., and to the HHMI for a predictorial fellowship to E.E.B.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
National Research Service AwardUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
J. Edward RichterUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Record Number:CaltechAUTHORS:20150609-092314492
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20150609-092314492
Official Citation:Recognition of the four Watson–Crick base pairs in the DNA minor groove by synthetic ligands Sarah White, Jason W. Szewczyk, James M. Turner, Eldon E. Baird and Peter B. Dervan Nature 391, 468-471 (29 January 1998)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58104
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Jun 2015 17:34
Last Modified:09 Jun 2015 17:34

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