Diversity in DNA recognition by p53 revealed by crystal structures with Hoogsteen base pairs.
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.
Kitayner
Malka
M
Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
Rozenberg
Haim
H
Rohs
Remo
R
Suad
Oded
O
Rabinovich
Dov
D
Honig
Barry
B
Shakked
Zippora
Z
D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D004247:DNA