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Targeted chemical wedges reveal the role of allosteric DNA modulation in protein-DNA assembly

Moretti, Rocco and Donato, Leslie J. and Brezinski, Mary L. and Stafford, Ryan L. and Hoff, Helena and Thorson, Jon S. and Dervan, Peter B. and Ansari, Aseem Z. (2008) Targeted chemical wedges reveal the role of allosteric DNA modulation in protein-DNA assembly. ACS Chemical Biology, 3 (4). pp. 220-229. ISSN 1554-8929. PMCID PMC3060767.

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The cooperative assembly of multiprotein complexes results from allosteric modulations of DNA structure as well as direct intermolecular contacts between proteins. Such cooperative binding plays a critical role in imparting exquisite sequence specificity on the homeobox transcription factor (Hox) family of developmental transcription factors. A well-characterized example includes the interaction of Hox proteins with extradenticle (Exd), a highly conserved DNA binding transcription factor. Although direct interactions are important, the contribution of indirect interactions toward cooperative assembly of Hox and Exd remains unresolved. Here we use minor groove binding polyamides as structural wedges to induce perturbations at specific base steps within the Exd binding site. We find that allosteric modulation of DNA structure contributes nearly 1.5 kcal/mol to the binding of Exd to DNA, even in the absence of direct Hox contacts. In contrast to previous studies, the sequence-targeted chemical wedges reveal the role of DNA geometry in cooperative assembly of Hox-Exd complexes. Programmable polyamides may well serve as general probes to investigate the role of DNA modulation in the cooperative and highly specific assembly of other protein-DNA complexes.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2008 American Chemical Society. Received for review December 18, 2007 and accepted February 17, 2008. We gratefully acknowledge the support of the NIH (GM069420 to A.Z.A., GM27681 to P.B.D., and AI552218 to J.S.T.), March of Dimes and W. M. Keck Foundations (to A.Z.A.), and the Shaw Scholar and Vilas Associate awards (to A.Z.A.). R.M. was supported by the NIH-MBTG predoctoral fellowship, L.D. was supported by the NLM-GSTP postdoctoral fellowship, and H.H. was an NSF-REU scholar.
Funding AgencyGrant Number
March of Dimes FoundationUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Vilas Associate AwardUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
NIH Postdoctoral FellowshipUNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC3060767
Record Number:CaltechAUTHORS:20160509-104237315
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Official Citation:Targeted Chemical Wedges Reveal the Role of Allosteric DNA Modulation in Protein−DNA Assembly Rocco Moretti, Leslie J. Donato, Mary L. Brezinski, Ryan L. Stafford, Helena Hoff, Jon S. Thorson, Peter B. Dervan, and Aseem Z. Ansari ACS Chemical Biology 2008 3 (4), 220-229 DOI: 10.1021/cb700258r
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66738
Deposited By: Victoria Brennan
Deposited On:17 May 2016 19:56
Last Modified:26 Nov 2019 11:15

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