Chenoweth, David M. and Dervan, Peter B. (2009) Allosteric modulation of DNA by small molecules. Proceedings of the National Academy of Sciences of the United States of America, 106 (32). pp. 13175-13179. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:20090901-162655528
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Many human diseases are caused by dysregulated gene expression. The oversupply of transcription factors may be required for the growth and metastatic behavior of human cancers. Cell permeable small molecules that can be programmed to disrupt transcription factor-DNA interfaces could silence aberrant gene expression pathways. Pyrrole-imidazole polyamides are DNA minor-groove binding molecules that are programmable for a large repertoire of DNA motifs. A high resolution X-ray crystal structure of an 8-ring cyclic Py/Im polyamide bound to the central 6 bp of the sequence d(5′-CCAGGCCTGG-3′)2 reveals a 4 Å widening of the minor groove and compression of the major groove along with a >18 ° bend in the helix axis toward the major groove. This allosteric perturbation of the DNA helix provides a molecular basis for disruption of transcription factor-DNA interfaces by small molecules, a minimum step in chemical control of gene networks.
|Additional Information:||Copyright ©2009 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Peter B. Dervan, June 17, 2009 (received for review April 20, 2009). Published online before print July 30, 2009, doi: 10.1073/pnas.0906532106 Synchrotron data were collected at Stanford Synchrotron Radiation Laboratory (SSRL) beamlines 11–1 and 12–2. We thank Douglas Rees valuable discussions, Jens Kaiser and Michael Day for their guidance with data collection and structure determination, and the staff of the SSRL for their assistance during crystal screening and data collection. Operations at SSRL are supported by the U.S. Department of Energy and the National Institutes of Health. We acknowledge the Gordon and Betty Moore Foundation for support of the Molecular Observatory at Caltech. This work was supported by National Institutes of Health and a Kanel Foundation predoctoral fellowship (to D.M.C.). Author contributions: D.M.C. performed research; D.M.C. and P.B.D. analyzed the data; and D.M.C. and P.B.D. wrote the paper. The authors declare no conflict of interest. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3I5L and 3I5E). This article contains supporting information online at www.pnas.org/cgi/content/full/0906532106/DCSupplemental.|
|Subject Keywords:||DNA binders; gene regulation; minor groove binders; Py-Im polyamides; crystal structure|
|Usage Policy:||Freely available online through the PNAS open access option.|
|Deposited By:||George Porter|
|Deposited On:||08 Sep 2009 21:41|
|Last Modified:||26 Dec 2012 11:18|
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