Factors governing loss and rescue of DNA binding upon single and double mutations in the p53 core domain

Nucleic Acids Research
Jon D WrightCarmay Lim

Abstract

The mutation of R273-->H in the p53 core domain (p53-CD) is one of the most common mutations found in human cancers. Although the 273H p53-CD retains the wild-type conformation and stability, it lacks sequence-specific DNA binding, a transactivation function and growth suppression. However, mutating T284-->R in the 273H p53-CD restores the DNA binding affinity, and transactivation and tumour suppressor functions. Since X-ray/NMR structures of DNA-free or DNA-bound mutant p53-CD molecules are unavailable, the factors governing the loss and rescue of sequence-specific DNA binding in the 273H and 273H+284R p53-CD, respectively, are unclear. Hence, we have carried out molecular dynamics (MD) simulations of the wild-type, single mutant and double mutant p53-CD, free and DNA bound, in the presence of explicit water molecules. Based on the MD structures, the DNA-binding free energy of each p53 molecule has been computed and decomposed into component energies and contributions from the interface residues. The wild-type and mutant p53-CD MD structures were found to be consistent with the antibody-binding, X-ray and NMR data. The predicted DNA binding affinity and specificity of both mutant p53-CDs were also in accord with experimental d...Continue Reading

References

Apr 1, 1992·Nature Genetics·W S el-DeiryB Vogelstein
Jul 5, 1991·Science·M HollsteinC C Harris
Feb 14, 1971·Journal of Molecular Biology·B Lee, F M Richards
Jan 1, 1984·Annual Review of Biophysics and Bioengineering·G A Petsko, D Ringe
May 1, 1994·Nature Structural Biology·R L Dunbrack, M Karplus
Jul 20, 1993·Journal of Molecular Biology·V Daggett, M Levitt
Dec 1, 1994·Nature Structural Biology·W LeeC H Arrowsmith
Mar 15, 1994·Proceedings of the National Academy of Sciences of the United States of America·J A PietenpolB Vogelstein
May 1, 1996·Genes & Development·L J Ko, C Prives
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
Oct 11, 1996·The Journal of Biological Chemistry·P FriedlanderC Prives
Oct 1, 1996·Nature Medicine·A M WieczorekT D Halazonetis
Aug 30, 1996·Biophysical Chemistry·K A Sharp
Feb 7, 1998·Proceedings of the National Academy of Sciences of the United States of America·A N BullockA R Fersht
Sep 2, 1998·Protein Engineering·J D Wright, C Lim
Jul 21, 1999·Proceedings of the National Academy of Sciences of the United States of America·K B WongA R Fersht
Jan 11, 2000·Nucleic Acids Research·R NifosìP A Kollman
Jul 21, 2001·Biophysical Journal·S Y Noskov, C Lim
Aug 28, 2001·Protein Engineering·J D Wright, C Lim

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Citations

Nov 21, 2013·Journal of Molecular Modeling·Shruti KoulgiRajendra Joshi
Oct 5, 2007·Journal of Biosciences·Jon D Wright, Carmay Lim
Mar 20, 2008·BMC Bioinformatics·Arumugam MadhumalarChandra Verma
Mar 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Buyong MaRuth Nussinov
Jan 1, 2015·Progress in Biophysics and Molecular Biology·Taniya SahaGaurisankar Sa
Apr 10, 2007·International Journal of Cancer. Journal International Du Cancer·Kazunori OtsukaChikashi Ishioka
Nov 16, 2010·Physical Chemistry Chemical Physics : PCCP·Teng WangXizeng Feng
Feb 7, 2019·Journal of Molecular Cell Biology·Yaw Sing TanChandra S Verma
Apr 14, 2018·International Journal of Molecular Sciences·Ana Sara GomesAna Luísa Carvalho
Sep 20, 2019·Biochimica Et Biophysica Acta. General Subjects·Ana Sara GomesLucília Saraiva

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