Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53
| Autor: | Peter K. Kaiser, Rommie E. Amaro, A. Richard Chamberlin, Brad D. Wallentine, Faezeh Salehi, Dawei Lin, Hartmut Luecke, Chiung-Kuang Chen, Roberta Baronio, Christopher D. Wassman, Linda V. Hall, Özlem Demir, Richard H. Lathrop, Benjamin P. Chung, G. Wesley Hatfield |
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| Rok vydání: | 2013 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Transcription Genetic Mutant General Physics and Astronomy Molecular Dynamics Simulation Biology Heterocyclic Compounds 4 or More Rings Protein Structure Secondary Article General Biochemistry Genetics and Molecular Biology law.invention Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Protein structure law Transcription (biology) Cell Line Tumor Proto-Oncogene Proteins Humans Structure–activity relationship Cysteine Binding site Gene 030304 developmental biology Aza Compounds 0303 health sciences Binding Sites Multidisciplinary Protein Stability Computational Biology Reproducibility of Results General Chemistry Bridged Bicyclo Compounds Heterocyclic Molecular biology Protein Structure Tertiary 3. Good health Cell culture 030220 oncology & carcinogenesis Oxepins Suppressor Mutant Proteins Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. About 40% of human cancers carry missense mutations in the tumour suppressor protein p53. Here the authors identify a transiently open pocket in the protein, and by targeting a small molecule to it, partially restore mutant p53 tumour suppressor activity. |
| Databáze: | OpenAIRE |
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