期刊
NUCLEIC ACIDS RESEARCH
卷 42, 期 4, 页码 2789-2797出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1219
关键词
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资金
- NIH [GM069557, RR028992, U01GM103804, R01HG003008, R01GM064642, 2U54RR022220]
- NSF [MCB-0546529, CHE-1213673]
- NSF
- NIH
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1213673] Funding Source: National Science Foundation
The tumor suppressor protein p53 regulates numerous signaling pathways by specifically recognizing diverse p53 response elements (REs). Understanding the mechanisms of p53-DNA interaction requires structural information on p53 REs. However, such information is limited as a 3D structure of any RE in the unbound form is not available yet. Here, site-directed spin labeling was used to probe the solution structures of REs involved in p53 regulation of the p21 and Bax genes. Multiple nanometer distances in the p21-RE and BAX-RE, measured using a nucleotide-independent nitroxide probe and double-electron-electron-resonance spectroscopy, were used to derive molecular models of unbound REs from pools of all-atom structures generated by Monte-Carlo simulations, thus enabling analyses to reveal sequence-dependent DNA shape features of unbound REs in solution. The data revealed distinct RE conformational changes on binding to the p53 core domain, and support the hypothesis that sequence-dependent properties encoded in REs are exploited by p53 to achieve the energetically most favorable mode of deformation, consequently enhancing binding specificity. This work reveals mechanisms of p53-DNA recognition, and establishes a new experimental/computational approach for studying DNA shape in solution that has far-reaching implications for studying protein-DNA interactions.
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