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A pyrrole-imidazole polyamide motif for recognition of eleven base pair sequences in the minor groove of DNA

Swalley, Susanne E. and Baird, Eldon E. and Dervan, Peter B. (1997) A pyrrole-imidazole polyamide motif for recognition of eleven base pair sequences in the minor groove of DNA. Chemistry: a European Journal, 3 (10). pp. 1600-1607. ISSN 0947-6539. doi:10.1002/chem.19970031009.

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A new upper limit of binding site size is defined for the 2:1 overlapped polyamide:DNA motif. Eight-ring polyamides composed of four-ring subunits containing pyrrole (Py) and imidazole (Im) amino acids linked by a central beta-alanine (beta) spacer (''4-beta-4 ligands'') were designed for recognition of eleven base pair sequences as antiparallel dimer (4-beta-4)(2) DNA complexes in the minor groove. The DNA binding properties of three polyamides, ImPyPyPy-beta-PyPyPyPy-beta-Dp, ImImPyPy-beta-PyPyPyPy-beta-Dp, and ImImImPy-beta-PyPyPyPy-beta-Dp, were analyzed by footprinting experiments on DNA fragments containing the respective match sites 5'-AGTAATTTACT-3', 5'-AGGTATTACCT-3' (Dp = dimethylaminopropylamide). Quantitative footprint titrations reveal that each polyamide binds its respective target site with subnanomolar affinity and 7-fold to over 30-fold specificity over double-base-pair mismatch sites. A 20-fold decrease in binding affinity is observed for placement of a side-by-side beta-beta pairing opposite G•C/C•G relative to placement opposite a A•T/T•A base pair. The use of side-by-side antiparallel beta-alanine residues as an A•T/T•A-specific DNA binding element provides a new pairing rule for polyamide design. Expanding the DNA binding site size targeted by pyrrole-imidazole polyamides represents an important step in the development of cell-permeable synthetic ligands for the control of gene-specific regulation.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1997 WILEY-VCH Verlag. Received: April 28, 1997. Dedicated to Dieter Seebach on the occasion of his 60th birthday. We are grateful to the National Institutes of Health (GM-27681) for research support, the National Institutes of Health for a research traineeship award (GM-08501) to S. E. S., and the Howard Hughes Medical Institute for a predoctoral fellowship to E. E. B.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM-08501
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:DNA recognition; hydrogen bonds; ligand design; molecular recognition; sequence-specificity
Issue or Number:10
Record Number:CaltechAUTHORS:20160510-100949983
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Official Citation:Swalley, S. E., Baird, E. E. and Dervan, P. B. (1997), A Pyrrole-Imidazole Polyamide Motif for Recognition of Eleven Base Pair Sequences in the Minor Groove of DNA. Chem. Eur. J., 3: 1600–1607. doi:10.1002/chem.19970031009
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66872
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:25
Last Modified:11 Nov 2021 00:23

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