Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket
The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/105824 http://hdl.handle.net/10220/48748 |
| _version_ | 1811695163476541440 |
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| author | Siau, Jia Wei Kannan, Srinivasaraghavan Ouaray, Zohra Kwoh, Chee Keong Ghadessy, Farid Pradhan, Mohan Rajan Nguyen, Minh N. Lane, David P. Verma, Chandra Shekhar |
| author2 | School of Computer Science and Engineering |
| author_facet | School of Computer Science and Engineering Siau, Jia Wei Kannan, Srinivasaraghavan Ouaray, Zohra Kwoh, Chee Keong Ghadessy, Farid Pradhan, Mohan Rajan Nguyen, Minh N. Lane, David P. Verma, Chandra Shekhar |
| author_sort | Siau, Jia Wei |
| collection | NTU |
| description | The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects. Inspired by the hypothesis that structural changes that are associated with events initiating unfolding in DBD are likely to present opportunities for inhibition, we investigate the dynamics of the wild type (WT) and some aggregating mutants through extensive all atom explicit solvent MD simulations. Simulations reveal differential conformational sampling between the WT and the mutants of a turn region (S6–S7) that is contiguous to a known aggregation-prone region (APR). The conformational properties of the S6–S7 turn appear to be modulated by a network of interacting residues. We speculate that changes that take place in this network as a result of the mutational stress result in the events that destabilize the DBD and initiate unfolding. These perturbations also result in the emergence of a novel pocket that appears to have druggable characteristics. FDA approved drugs are computationally screened against this pocket. |
| first_indexed | 2024-10-01T07:19:06Z |
| format | Journal Article |
| id | ntu-10356/105824 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:19:06Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1058242023-02-28T17:06:33Z Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket Siau, Jia Wei Kannan, Srinivasaraghavan Ouaray, Zohra Kwoh, Chee Keong Ghadessy, Farid Pradhan, Mohan Rajan Nguyen, Minh N. Lane, David P. Verma, Chandra Shekhar School of Computer Science and Engineering School of Biological Sciences DNA Binding Domain P53 DRNTU::Science::Biological sciences The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects. Inspired by the hypothesis that structural changes that are associated with events initiating unfolding in DBD are likely to present opportunities for inhibition, we investigate the dynamics of the wild type (WT) and some aggregating mutants through extensive all atom explicit solvent MD simulations. Simulations reveal differential conformational sampling between the WT and the mutants of a turn region (S6–S7) that is contiguous to a known aggregation-prone region (APR). The conformational properties of the S6–S7 turn appear to be modulated by a network of interacting residues. We speculate that changes that take place in this network as a result of the mutational stress result in the events that destabilize the DBD and initiate unfolding. These perturbations also result in the emergence of a novel pocket that appears to have druggable characteristics. FDA approved drugs are computationally screened against this pocket. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2019-06-14T02:35:53Z 2019-12-06T21:58:42Z 2019-06-14T02:35:53Z 2019-12-06T21:58:42Z 2019 Journal Article Pradhan, M. R., Siau, J. W., Kannan, S., Nguyen, M. N., Ouaray, Z., Kwoh, C. K., . . . Verma, C. S. (2019). Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket. Nucleic Acids Research, 47(4), 1637-1652. doi:10.1093/nar/gky1314 0305-1048 https://hdl.handle.net/10356/105824 http://hdl.handle.net/10220/48748 10.1093/nar/gky1314 en Nucleic Acids Research © 2019 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 16 p. application/pdf |
| spellingShingle | DNA Binding Domain P53 DRNTU::Science::Biological sciences Siau, Jia Wei Kannan, Srinivasaraghavan Ouaray, Zohra Kwoh, Chee Keong Ghadessy, Farid Pradhan, Mohan Rajan Nguyen, Minh N. Lane, David P. Verma, Chandra Shekhar Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title | Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title_full | Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title_fullStr | Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title_full_unstemmed | Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title_short | Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket |
| title_sort | simulations of mutant p53 dna binding domains reveal a novel druggable pocket |
| topic | DNA Binding Domain P53 DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/105824 http://hdl.handle.net/10220/48748 |
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