Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2009-6-22
pubmed:abstractText
The core domain of the tumour suppressor p53 is of inherently low thermodynamic stability and also low kinetic stability, which leads to rapid irreversible denaturation. Some oncogenic mutations of p53 act by just making the core domain thermosensitive, and so it is the target of novel anti-cancer drugs that bind to and stabilise the protein. Increasing the stability of the unstable core domain has also been crucial for biophysical and structural studies, in which a stabilised quadruple mutant (QM) is currently used. We generated an even more stabilised hexamutant (HM) by making two additional substitutions, Y236F and T253I, to the QM. The residues are found in the more stable paralogs p63 and p73 and stabilise the wild-type p53 core domain. We solved the structure of the HM core domain by X-ray crystallography at 1.75 A resolution. It has minimal structural changes from QM that affect the packing of hydrophobic core residues of the beta-sandwich. The full-length HM was also fully functional in DNA binding. HM was more stable than QM at 37 degrees C. Anomalies in biophysics and spectroscopy in urea-mediated denaturation curves of HM implied the accumulation of a folding intermediate, which may be related to those detected in kinetic experiments. The two additional mutations over-stabilise an unfolding intermediate. These results should be taken into consideration in drug design strategies for increasing the stability of temperature-sensitive mutants of p53.
pubmed:grant
pubmed:commentsCorrections
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pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1741-0134
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
421-30
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Stabilising the DNA-binding domain of p53 by rational design of its hydrophobic core.
pubmed:affiliation
MRC Centre for Protein Engineering, Cambridge, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't