Journal Article

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

Richard Chamberlin, A., Baronio, Roberta, Kaiser, Peter, Amaro, Rommie E., Lin, Da-Wei, Wallentine, Brad D., Wesley Hatfield, G., Wassman, Christopher D., Demir, Özlem, Chung, Benjamin P., Salehi, Faezeh, Chen, Chiung-Kuang, Lathrop, Richard H., Hall, Linda V., Luecke, Hartmut

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 631/114 / 631/67/581 / 692/308 / Apoptosis Regulatory Proteins - metabolism / Aza Compounds - pharmacology / Binding Sites / Biochemistry / Bone cancer / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Cell cycle / Cell growth / Cell Line, Tumor / Chemistry / Computational Biology - methods / Crystal structure / Cyclin-Dependent Kinase Inhibitor p21 - genetics / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cysteine - genetics / Heterocyclic Compounds, 4 or More Rings - chemistry / Heterocyclic Compounds, 4 or More Rings - pharmacology / Humanities and Social Sciences / Humans / Molecular Dynamics Simulation / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - metabolism / Mutants / Mutation / NMR / Nuclear magnetic resonance / Oxepins - chemistry / Oxepins - pharmacology / Pharmaceuticals / Protein Stability - drug effects / Protein Structure, Secondary / Protein Structure, Tertiary / Proteins / Proto-Oncogene Proteins - metabolism / Reproducibility of Results / Science / Science (multidisciplinary) / Structure-Activity Relationship / Transcription, Genetic - drug effects / Tumor Suppressor Protein p53 - chemistry / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors