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Dinesh, Goswami A, Suresh PS, et al. Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions. Bioinformation. 2011;7(1):21-8
Dinesh, Goswami, A., Suresh, P. S., Thirunavukkarasu, C., Weiergräber, O. H., & Kumar, M. S. (2011). Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions. Bioinformation, 7(1), 21-8.
Dinesh, et al. "Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions." Bioinformation vol. 7,1 (2011): 21-8.
Dinesh, Goswami A, Suresh PS, Thirunavukkarasu C, Weiergräber OH, Kumar MS. Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions. Bioinformation. 2011;7(1):21-8. Epub 2011 Aug 20. PMID: 21904434; PMCID: PMC3163928.
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Bioinformation. 2011;7(1):21-8. Epub 2011 Aug 20.

Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions.

Bioinformation

Dinesh, Angshumala Goswami, Panneer Selvam Suresh, Chinnasamy Thirunavukkarasu, Oliver H Weiergräber, Muthuvel Suresh Kumar

PMID: 21904434 PMCID: PMC3163928

Abstract

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.

References

  1. J Clin Invest. 2001 Jul;108(1):143-51 - PubMed
  2. Cell. 1993 Jan 29;72(2):269-78 - PubMed
  3. Annu Rev Biochem. 1998;67:27-48 - PubMed
  4. Cold Spring Harb Symp Quant Biol. 1986;51 Pt 1:597-609 - PubMed
  5. J Biol Chem. 2002 Jul 19;277(29):25847-50 - PubMed
  6. Neurochem Res. 2002 Aug;27(7-8):601-7 - PubMed
  7. FEBS Lett. 2002 Oct 30;531(1):38-46 - PubMed
  8. J Lipid Res. 1976 Sep;17(5):506-15 - PubMed
  9. Cell. 1994 Sep 23;78(6):1005-15 - PubMed
  10. Eur J Biochem. 1988 Aug 1;175(2):213-20 - PubMed
  11. EMBO J. 1999 May 4;18(9):2472-9 - PubMed
  12. J Biol Chem. 1999 Dec 31;274(53):38131-9 - PubMed
  13. J Biol Chem. 1991 Jul 25;266(21):13519-29 - PubMed
  14. Biochem Cell Biol. 2004 Feb;82(1):27-44 - PubMed
  15. Science. 1993 Mar 19;259(5102):1769-71 - PubMed
  16. Cell. 1996 Sep 20;86(6):937-47 - PubMed
  17. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5895-900 - PubMed
  18. J Cell Biol. 1994 Jul;126(1):5-9 - PubMed
  19. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3638-43 - PubMed
  20. Trends Biochem Sci. 1998 Oct;23(10):374-7 - PubMed
  21. J Lipid Res. 1967 May;8(3):202-9 - PubMed

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