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NMR structure of a cyclic polyamide-DNA complex

Zhang, Qing and Dwyer, Tammy J. and Tsui, Vickie and Case, David A. and Cho, Junhyeong and Dervan, Peter B. and Wemmer, David E. (2004) NMR structure of a cyclic polyamide-DNA complex. Journal of the American Chemical Society, 126 (25). pp. 7958-7966. ISSN 0002-7863. doi:10.1021/ja0373622.

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The solution structure of a cyclic polyamide ligand complexed to a DNA oligomer, derived from NMR restrained molecular mechanics, is presented. The polyamide, cyclo-gamma-ImPyPy-gamma-PyPyPy-, binds to target DNA with a nanomolar dissociation constant as characterized by quantitative footprinting previously reported. 2D (1)H NMR data were used to generate distance restraints defining the structure of this cyclic polyamide with the DNA duplex d(5'-GCCTGTTAGCG-3'):d(5'-CGCTAACAGGC-3'). Data interpretation used complete relaxation matrix analysis of the NOESY cross-peak intensities with the program MARDIGRAS. The NMR-based distance restraints (276 total) were applied in restrained molecular dynamics calculations using a solvent model, yielding structures with an rmsd for the ligand and binding site of approximately 1 A. The resulting structures indicate some distortion of the DNA in the binding site. The constraints from cyclization lead to altered stacking of the rings in the halves of the cyclic ligand relative to unlinked complexes. Despite this, the interactions with DNA are very similar to what has been found in unlinked complexes. Measurements of ligand amide and DNA imino proton exchange rates indicate very slow dissociation of the ligand and show that the DNA can undergo opening fluctuations while the ligand is bound although the presence of the ligand decreases their frequency relative to the free DNA.

Item Type:Article
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URLURL TypeDescription Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 American Chemical Society. Received July 17, 2003. Publication Date (Web): June 2, 2004. This work was supported by NIH grants GM45811 (to D.A.C.) and GM43129 (to D.E.W.), and GM 27681 (to P.B.D.), and F33 GM63420 (to T.J.D.).
Funding AgencyGrant Number
NIH Postodctoral FellowshipF33 GM63420
Issue or Number:25
Record Number:CaltechAUTHORS:20160509-114912154
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Official Citation:NMR Structure of a Cyclic Polyamide−DNA Complex Qing Zhang, Tammy J. Dwyer, Vickie Tsui, David A. Case, Junhyeong Cho, Peter B. Dervan, and David E. Wemmer Journal of the American Chemical Society 2004 126 (25), 7958-7966 DOI: 10.1021/ja0373622
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66770
Deposited By: Victoria Brennan
Deposited On:17 May 2016 23:06
Last Modified:11 Nov 2021 00:02

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