Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 4, Pages 423-U58Publisher
NATURE PORTFOLIO
DOI: 10.1038/nsmb.1800
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Funding
- Israel Science Foundation [954/08]
- Kimmelman Center for Biomolecular Structure and Assembly
- EC
- German-Israeli Foundation for Scientific Research Development
- Minerva Foundation
- Federal German Ministry of Education and Research
- US National Institutes of Health [U54 CA121852]
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p53 binds as a tetramer to DNA targets consisting of two decameric half-sites separated by a variable spacer. Here we present high-resolution crystal structures of complexes between p53 core-domain tetramers and DNA targets consisting of contiguous half-sites. In contrast to previously reported p53-DNA complexes that show standard Watson-Crick base pairs, the newly reported structures show noncanonical Hoogsteen base-pairing geometry at the central A-T doublet of each half-site. Structural and computational analyses show that the Hoogsteen geometry distinctly modulates the B-DNA helix in terms of local shape and electrostatic potential, which, together with the contiguous DNA configuration, results in enhanced protein-DNA and protein-protein interactions compared to noncontiguous half-sites. Our results suggest a mechanism relating spacer length to protein-DNA binding affinity. Our findings also expand the current understanding of protein-DNA recognition and establish the structural and chemical properties of Hoogsteen base pairs as the basis for a novel mode of sequence readout.
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