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Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer
O(6)-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O(6)-methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterati...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444098/ https://www.ncbi.nlm.nih.gov/pubmed/26011121 http://dx.doi.org/10.1371/journal.pone.0127741 |
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author | Chikan, Naveed Anjum Bukhari, Shoiab Shabir, Nadeem Amin, Asif Shafi, Sheikh Qadri, Raies Ahmad Patel, Trupti Navin Chandra |
author_facet | Chikan, Naveed Anjum Bukhari, Shoiab Shabir, Nadeem Amin, Asif Shafi, Sheikh Qadri, Raies Ahmad Patel, Trupti Navin Chandra |
author_sort | Chikan, Naveed Anjum |
collection | PubMed |
description | O(6)-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O(6)-methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations in the form of nucleotide polymorphism may result in altered protein structure that in turn can lead to the loss of function. In the present study, we focused on the population feared for high exposure to alkylating agents owing to their typical and specialized dietary habits. To this end, gastric cancer patients pooled out from the population were selected for the mutational screening of a specific error prone region of MGMT gene. We found that nearly 40% of the studied neoplastic samples harbored missense mutation at codon(151) resulting into Serine to Isoleucine variation. This variation resulted in bringing about the structural disorder, subsequently ensuing into a major stoichiometric variance in recognition domain, substrate binding and selectivity loop of the active site of the MGMT protein, as observed under virtual microscope of molecular dynamics simulation (MDS). The atomic insight into MGMT protein by computational approach showed a significant change in the intra molecular hydrogen bond pattern, thus leading to the observed structural anomalies. To further examine the mutational implications on regulatory plugs of MGMT that holds the protein in a DNA-Binding position, a MDS based analysis was carried out on, all known physically interacting amino acids essentially clustered into groups based on their position and function. The results generated by physical-functional clustering of protein indicated that the identified mutation in the vicinity of the active site of MGMT protein causes the local and global destabilization of a protein by either eliminating the stabilizing salt bridges in cluster C3, C4, and C5 or by locally destabilizing the “protein stabilizing hing” mapped on C3-C4 cluster, preceding the active site. |
format | Online Article Text |
id | pubmed-4444098 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44440982015-06-16 Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer Chikan, Naveed Anjum Bukhari, Shoiab Shabir, Nadeem Amin, Asif Shafi, Sheikh Qadri, Raies Ahmad Patel, Trupti Navin Chandra PLoS One Research Article O(6)-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O(6)-methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations in the form of nucleotide polymorphism may result in altered protein structure that in turn can lead to the loss of function. In the present study, we focused on the population feared for high exposure to alkylating agents owing to their typical and specialized dietary habits. To this end, gastric cancer patients pooled out from the population were selected for the mutational screening of a specific error prone region of MGMT gene. We found that nearly 40% of the studied neoplastic samples harbored missense mutation at codon(151) resulting into Serine to Isoleucine variation. This variation resulted in bringing about the structural disorder, subsequently ensuing into a major stoichiometric variance in recognition domain, substrate binding and selectivity loop of the active site of the MGMT protein, as observed under virtual microscope of molecular dynamics simulation (MDS). The atomic insight into MGMT protein by computational approach showed a significant change in the intra molecular hydrogen bond pattern, thus leading to the observed structural anomalies. To further examine the mutational implications on regulatory plugs of MGMT that holds the protein in a DNA-Binding position, a MDS based analysis was carried out on, all known physically interacting amino acids essentially clustered into groups based on their position and function. The results generated by physical-functional clustering of protein indicated that the identified mutation in the vicinity of the active site of MGMT protein causes the local and global destabilization of a protein by either eliminating the stabilizing salt bridges in cluster C3, C4, and C5 or by locally destabilizing the “protein stabilizing hing” mapped on C3-C4 cluster, preceding the active site. Public Library of Science 2015-05-26 /pmc/articles/PMC4444098/ /pubmed/26011121 http://dx.doi.org/10.1371/journal.pone.0127741 Text en © 2015 Chikan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Chikan, Naveed Anjum Bukhari, Shoiab Shabir, Nadeem Amin, Asif Shafi, Sheikh Qadri, Raies Ahmad Patel, Trupti Navin Chandra Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title | Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title_full | Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title_fullStr | Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title_full_unstemmed | Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title_short | Atomic Insight into the Altered O(6)-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer |
title_sort | atomic insight into the altered o(6)-methylguanine-dna methyltransferase protein architecture in gastric cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444098/ https://www.ncbi.nlm.nih.gov/pubmed/26011121 http://dx.doi.org/10.1371/journal.pone.0127741 |
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