2fej
From Proteopedia
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[[Image:2fej.gif|left|200px]] | [[Image:2fej.gif|left|200px]] | ||
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'''Solution structure of human p53 DNA binding domain.''' | '''Solution structure of human p53 DNA binding domain.''' | ||
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[[Category: Rutherford, T J.]] | [[Category: Rutherford, T J.]] | ||
[[Category: Tidow, H.]] | [[Category: Tidow, H.]] | ||
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Revision as of 00:48, 4 May 2008
Solution structure of human p53 DNA binding domain.
Overview
The 25-kDa core domain of the tumor suppressor p53 is inherently unstable and melts at just above body temperature, which makes it susceptible to oncogenic mutations that inactivate it by lowering its stability. We determined its structure in solution using state-of-the-art isotopic labeling techniques and NMR spectroscopy to complement its crystal structure. The structure was very similar to that in the crystal but far more mobile than expected. Importantly, we were able to analyze by NMR the structural environment of several buried polar groups, which indicated structural reasons for the instability. NMR spectroscopy, with its ability to detect protons, located buried hydroxyl and sulfhydryl groups that form suboptimal hydrogen-bond networks. We mutated one such buried pair, Tyr-236 and Thr-253 to Phe-236 and Ile-253 (as found in the paralogs p63 and p73), and stabilized p53 by 1.6 kcal/mol. We also detected differences in the conformation of a mobile loop that might reflect the existence of physiologically relevant alternative conformations. The effects of temperature on the dynamics of aromatic residues indicated that the protein also experiences several dynamic processes that might be related to the presence of alternative hydrogen-bond patterns in the protein interior. p53 appears to have evolved to be dynamic and unstable.
About this Structure
2FEJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Solution structure of p53 core domain: structural basis for its instability., Canadillas JM, Tidow H, Freund SM, Rutherford TJ, Ang HC, Fersht AR, Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2109-14. Epub 2006 Feb 6. PMID:16461916 Page seeded by OCA on Sun May 4 03:48:14 2008
