Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53

Christopher D. Wassman, Roberta Baronio, Özlem Demir, Brad D. Wallentine, Chiung-Kuang Chen, Linda V. Hall, Faezeh Salehi, Da-Wei Lin, Benjamin P. Chung, G. Wesley Hatfield, A. Richard Chamberlin, Hartmut Luecke, Richard H. Lathrop, Peter Kaiser () and Rommie E. Amaro ()
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Christopher D. Wassman: University of California, Irvine
Roberta Baronio: Institute for Genomics and Bioinformatics, University of California, Irvine
Özlem Demir: University of California, Irvine
Brad D. Wallentine: University of California, Irvine
Chiung-Kuang Chen: University of California, Irvine
Linda V. Hall: Institute for Genomics and Bioinformatics, University of California, Irvine
Faezeh Salehi: University of California, Irvine
Da-Wei Lin: University of California, Irvine
Benjamin P. Chung: University of California, Irvine
G. Wesley Hatfield: Institute for Genomics and Bioinformatics, University of California, Irvine
A. Richard Chamberlin: University of California, Irvine
Hartmut Luecke: Institute for Genomics and Bioinformatics, University of California, Irvine
Richard H. Lathrop: University of California, Irvine
Peter Kaiser: Institute for Genomics and Bioinformatics, University of California, Irvine
Rommie E. Amaro: University of California, Irvine

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract The tumour suppressor p53 is the most frequently mutated gene in human cancer. Reactivation of mutant p53 by small molecules is an exciting potential cancer therapy. Although several compounds restore wild-type function to mutant p53, their binding sites and mechanisms of action are elusive. Here computational methods identify a transiently open binding pocket between loop L1 and sheet S3 of the p53 core domain. Mutation of residue Cys124, located at the centre of the pocket, abolishes p53 reactivation of mutant R175H by PRIMA-1, a known reactivation compound. Ensemble-based virtual screening against this newly revealed pocket selects stictic acid as a potential p53 reactivation compound. In human osteosarcoma cells, stictic acid exhibits dose-dependent reactivation of p21 expression for mutant R175H more strongly than does PRIMA-1. These results indicate the L1/S3 pocket as a target for pharmaceutical reactivation of p53 mutants.

Date: 2013
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DOI: 10.1038/ncomms2361

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