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Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Modulating DNA Binding Activity of p53 by Base Sequence Effects and Amino-Acid Mutations

Our structural studies of the DNA binding domain of the tumor suppressor protein p53 and its complexes with various DNA targets demonstrate that four p53 molecules bind to two decameric DNA half-sites to form a dimer of dimers stabilized by protein-DNA and protein-protein interactions. The 3-D architecture of the complex and its stability are dependent on the identity of the DNA half-sites and on the DNA spacer between them. Several hot-spot mutations in the DNA binding domain of p53 abolish the protein’s DNA binding activity and its function as a tumor suppressor. In certain cases, such activities can be restored by second-site suppressor mutations. Our high-resolution crystal structures of wild-type p53, its tumor-derived p53 mutants and the restored proteins in their free and DNA-bound states provide a framework for understanding the molecular and structural basis of p53 disfunction as a result of oncogenic mutations and its restoration by suppressor mutations and potential drug molecules.

H. Rozenberg
A. Eldar
M. Kitayner
Y. Diskin-Posner
A. Kapitkovsky
O. Suad
Z. Shakked

Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel

Ph: 972-8-9342672
Fx: 972-8-9346278

zippi.shakked@weizmann.ac.il