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Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions
The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Biomedical Informatics
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163928/ https://www.ncbi.nlm.nih.gov/pubmed/21904434 |
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author | Dinesh, Goswami, Angshumala Suresh, Panneer Selvam Thirunavukkarasu, Chinnasamy Weiergräber, Oliver H Kumar, Muthuvel Suresh |
author_facet | Dinesh, Goswami, Angshumala Suresh, Panneer Selvam Thirunavukkarasu, Chinnasamy Weiergräber, Oliver H Kumar, Muthuvel Suresh |
author_sort | Dinesh, |
collection | PubMed |
description | The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-terminus of the 55 kDa tumour necrosis factor receptor (TNF-R55), designated the neutral sphingomyelinase activating domain (NSD) that is responsible for the TNF-induced activation of N-SMase. There is no direct association between TNF-R55 NSD and N-SMase; instead, a protein named factor associated with N-SMase activation (FAN) has been reported to couple the TNF-R55 NSD to N-SMase. Since the three-dimensional fold of N-SMase is still unknown, we have modeled the structure using the protein fold recognition and threading method. Moreover, we propose models for the TNF-R55 NSD as well as the FAN protein in order to study the structural basis of N-SMase activation and regulation. Protein-protein interaction studies suggest that FAN is crucially involved in mediating TNF-induced activation of the N-SMase pathway, which in turn regulates mitogenic and proinflammatory responses. Inhibition of N-SMase may lead to reduction of ceramide levels and hence may provide a novel therapeutic strategy for inflammation and autoimmune diseases. Molecular dynamics (MD) simulations were performed to check the stability of the predicted model and protein-protein complex; indeed, stable RMS deviations were obtained throughout the simulation. Furthermore, in silico docking of low molecular mass ligands into the active site of N-SMase suggests that His135, Glu48, Asp177, and Asn179 residues play crucial roles in this interaction. Based on our results, these ligands are proposed to be potent and selective N-SMase inhibitors, which may ultimately prove useful as lead compounds for drug development. |
format | Online Article Text |
id | pubmed-3163928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Biomedical Informatics |
record_format | MEDLINE/PubMed |
spelling | pubmed-31639282011-09-08 Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions Dinesh, Goswami, Angshumala Suresh, Panneer Selvam Thirunavukkarasu, Chinnasamy Weiergräber, Oliver H Kumar, Muthuvel Suresh Bioinformation Hypothesis The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-terminus of the 55 kDa tumour necrosis factor receptor (TNF-R55), designated the neutral sphingomyelinase activating domain (NSD) that is responsible for the TNF-induced activation of N-SMase. There is no direct association between TNF-R55 NSD and N-SMase; instead, a protein named factor associated with N-SMase activation (FAN) has been reported to couple the TNF-R55 NSD to N-SMase. Since the three-dimensional fold of N-SMase is still unknown, we have modeled the structure using the protein fold recognition and threading method. Moreover, we propose models for the TNF-R55 NSD as well as the FAN protein in order to study the structural basis of N-SMase activation and regulation. Protein-protein interaction studies suggest that FAN is crucially involved in mediating TNF-induced activation of the N-SMase pathway, which in turn regulates mitogenic and proinflammatory responses. Inhibition of N-SMase may lead to reduction of ceramide levels and hence may provide a novel therapeutic strategy for inflammation and autoimmune diseases. Molecular dynamics (MD) simulations were performed to check the stability of the predicted model and protein-protein complex; indeed, stable RMS deviations were obtained throughout the simulation. Furthermore, in silico docking of low molecular mass ligands into the active site of N-SMase suggests that His135, Glu48, Asp177, and Asn179 residues play crucial roles in this interaction. Based on our results, these ligands are proposed to be potent and selective N-SMase inhibitors, which may ultimately prove useful as lead compounds for drug development. Biomedical Informatics 2011-08-20 /pmc/articles/PMC3163928/ /pubmed/21904434 Text en © 2011 Biomedical Informatics This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium, for non-commercial purposes, provided the original author and source are credited. |
spellingShingle | Hypothesis Dinesh, Goswami, Angshumala Suresh, Panneer Selvam Thirunavukkarasu, Chinnasamy Weiergräber, Oliver H Kumar, Muthuvel Suresh Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title | Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title_full | Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title_fullStr | Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title_full_unstemmed | Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title_short | Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
title_sort | molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions |
topic | Hypothesis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163928/ https://www.ncbi.nlm.nih.gov/pubmed/21904434 |
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