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