Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.

O6-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6-methylguanine (mutagenic lesion) back to guanine, eventually suppressing the mismatch errors and double strand crosslinks. Exonic alterations...

Full description

Bibliographic Details
Main Authors: Naveed Anjum Chikan, Shoiab Bukhari, Nadeem Shabir, Asif Amin, Sheikh Shafi, Raies Ahmad Qadri, Trupti Navin Chandra Patel
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2015-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC4444098?pdf=render
_version_ 1828876162414149632
author Naveed Anjum Chikan
Shoiab Bukhari
Nadeem Shabir
Asif Amin
Sheikh Shafi
Raies Ahmad Qadri
Trupti Navin Chandra Patel
author_facet Naveed Anjum Chikan
Shoiab Bukhari
Nadeem Shabir
Asif Amin
Sheikh Shafi
Raies Ahmad Qadri
Trupti Navin Chandra Patel
author_sort Naveed Anjum Chikan
collection DOAJ
description O6-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6-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 codon151 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.
first_indexed 2024-12-13T08:14:42Z
format Article
id doaj.art-0c06ced62dac4bc497eaa18a52a2efb0
institution Directory Open Access Journal
issn 1932-6203
language English
last_indexed 2024-12-13T08:14:42Z
publishDate 2015-01-01
publisher Public Library of Science (PLoS)
record_format Article
series PLoS ONE
spelling doaj.art-0c06ced62dac4bc497eaa18a52a2efb02022-12-21T23:54:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01105e012774110.1371/journal.pone.0127741Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.Naveed Anjum ChikanShoiab BukhariNadeem ShabirAsif AminSheikh ShafiRaies Ahmad QadriTrupti Navin Chandra PatelO6-methylguanine-DNA methyltransferase (MGMT) is one of the major DNA repair protein that counteracts the alkalyting agent-induced DNA damage by replacing O6-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 codon151 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.http://europepmc.org/articles/PMC4444098?pdf=render
spellingShingle Naveed Anjum Chikan
Shoiab Bukhari
Nadeem Shabir
Asif Amin
Sheikh Shafi
Raies Ahmad Qadri
Trupti Navin Chandra Patel
Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
PLoS ONE
title Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
title_full Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
title_fullStr Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
title_full_unstemmed Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
title_short Atomic Insight into the Altered O6-Methylguanine-DNA Methyltransferase Protein Architecture in Gastric Cancer.
title_sort atomic insight into the altered o6 methylguanine dna methyltransferase protein architecture in gastric cancer
url http://europepmc.org/articles/PMC4444098?pdf=render
work_keys_str_mv AT naveedanjumchikan atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT shoiabbukhari atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT nadeemshabir atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT asifamin atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT sheikhshafi atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT raiesahmadqadri atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer
AT truptinavinchandrapatel atomicinsightintothealteredo6methylguaninednamethyltransferaseproteinarchitectureingastriccancer