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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...

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Autores principales: Chikan, Naveed Anjum, Bukhari, Shoiab, Shabir, Nadeem, Amin, Asif, Shafi, Sheikh, Qadri, Raies Ahmad, Patel, Trupti Navin Chandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
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.
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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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