Anin silicoalgorithm for identifying stabilizing pockets in proteins: test case, the Y220C mutant of the p53 tumor suppressor protein
| Autor: | Valerie Daggett, Dennis Bromley, Alan R. Fersht, Matthias R. Bauer |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint In silico Mutant Bioengineering Molecular Dynamics Simulation Biology Ligands Biochemistry law.invention 03 medical and health sciences Protein Domains law DOCK Computer Simulation Denaturation (biochemistry) Molecular Biology Gene 030102 biochemistry & molecular biology Protein Stability Temperature DNA Small molecule Molecular Docking Simulation 030104 developmental biology Mutation Suppressor Original Article Tumor Suppressor Protein p53 Algorithm Algorithms Biotechnology |
| Zdroj: | Protein Engineering Design and Selection. 29:377-390 |
| ISSN: | 1741-0134 1741-0126 |
| Popis: | The p53 tumor suppressor protein performs a critical role in stimulating apoptosis and cell cycle arrest in response to oncogenic stress. The function of p53 can be compromised by mutation, leading to increased risk of cancer; approximately 50% of cancers are associated with mutations in the p53 gene, the majority of which are in the core DNA-binding domain. The Y220C mutation of p53, for example, destabilizes the core domain by 4 kcal/mol, leading to rapid denaturation and aggregation. The associated loss of tumor suppressor functionality is associated with approximately 75 000 new cancer cases every year. Destabilized p53 mutants can be 'rescued' and their function restored; binding of a small molecule into a pocket on the surface of mutant p53 can stabilize its wild-type structure and restore its function. Here, we describe an in silico algorithm for identifying potential rescue pockets, including the algorithm's integration with the Dynameomics molecular dynamics data warehouse and the DIVE visual analytics engine. We discuss the results of the application of the method to the Y220C p53 mutant, entailing finding a putative rescue pocket through MD simulations followed by an in silico search for stabilizing ligands that dock into the putative rescue pocket. The top three compounds from this search were tested experimentally and one of them bound in the pocket, as shown by nuclear magnetic resonance, and weakly stabilized the mutant. |
| Databáze: | OpenAIRE |
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