Author
Listed:
- Christopher D. Wassman
(University of California, Irvine
Institute for Genomics and Bioinformatics, University of California, Irvine
Present address: Google Inc., 1600 Amphitheatre Parkway Mountain View, California 94043, USA)
- Roberta Baronio
(Institute for Genomics and Bioinformatics, University of California, Irvine
University of California, Irvine)
- Özlem Demir
(University of California, Irvine
Present addresses: Department of Chemistry and Biochemistry, University of California, San Diego; La Jolla, California 92093, USA)
- 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
University of California, Irvine)
- Faezeh Salehi
(University of California, Irvine
Institute for Genomics and Bioinformatics, 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
University of California, Irvine
University of California, Irvine)
- A. Richard Chamberlin
(University of California, Irvine
University of California, Irvine
Chao Family Comprehensive Cancer Center, University of California, Irvine)
- Hartmut Luecke
(Institute for Genomics and Bioinformatics, University of California, Irvine
University of California, Irvine
Chao Family Comprehensive Cancer Center, University of California, Irvine
University of California, Irvine)
- Richard H. Lathrop
(University of California, Irvine
Institute for Genomics and Bioinformatics, University of California, Irvine
Chao Family Comprehensive Cancer Center, University of California, Irvine
University of California, Irvine)
- Peter Kaiser
(Institute for Genomics and Bioinformatics, University of California, Irvine
University of California, Irvine
Chao Family Comprehensive Cancer Center, University of California, Irvine)
- Rommie E. Amaro
(University of California, Irvine
University of California, Irvine
University of California, Irvine
Present addresses: Department of Chemistry and Biochemistry, University of California, San Diego; La Jolla, California 92093, USA)
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.
Suggested Citation
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 Chamb, 2013.
"Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53,"
Nature Communications, Nature, vol. 4(1), pages 1-9, June.
Handle:
RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2361
DOI: 10.1038/ncomms2361
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