Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction
The ubiquitin ligase MDM2, a principle regulator of the tumor suppressor p53, plays an integral role in regulating cellular levels of p53 and thus a prominent role in current cancer research. Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive...
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| Veröffentlicht in: | PloS one 2016-03, Vol.11 (3), p.e0147806 |
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| description | The ubiquitin ligase MDM2, a principle regulator of the tumor suppressor p53, plays an integral role in regulating cellular levels of p53 and thus a prominent role in current cancer research. Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ΔΔG comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field. |
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Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ΔΔG comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0147806</identifier><identifier>PMID: 26992014</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Apoptosis ; Biology and Life Sciences ; Cancer ; Cell cycle ; Competition ; Computation ; Computational biology ; Computer applications ; Crystal structure ; Genetic aspects ; Genomes ; Humans ; Hydrophobicity ; MDM2 protein ; Medical research ; Medicine and Health Sciences ; Mutagenesis ; Mutation ; p53 Protein ; Peptides ; Physical Sciences ; Physiological aspects ; Protein Binding ; Proteins ; Proto-Oncogene Proteins c-mdm2 - chemistry ; Residues ; Tumor proteins ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - chemistry ; Ubiquitin ; Ubiquitin-protein ligase</subject><ispartof>PloS one, 2016-03, Vol.11 (3), p.e0147806</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Thayer, Beyer. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ΔΔG comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26992014</pmid><doi>10.1371/journal.pone.0147806</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Apoptosis Biology and Life Sciences Cancer Cell cycle Competition Computation Computational biology Computer applications Crystal structure Genetic aspects Genomes Humans Hydrophobicity MDM2 protein Medical research Medicine and Health Sciences Mutagenesis Mutation p53 Protein Peptides Physical Sciences Physiological aspects Protein Binding Proteins Proto-Oncogene Proteins c-mdm2 - chemistry Residues Tumor proteins Tumor suppressor genes Tumor Suppressor Protein p53 - chemistry Ubiquitin Ubiquitin-protein ligase |
| title | Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction |
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