A computational study of the oligosaccharide binding sites in the lectin-like domain of tumor necrosis factor and the TNF-derived TIP peptide

Alexander Dulebo, Rüdiger Ettrich, Rudolf Lucas, David Kaftan

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The lectin-like domain of Tumor Necrosis Factor (TNF), mimicked by the TIP peptide, activates amiloride-sensitive sodium uptake in type II alveolar epithelial cells and as such increases alveolar liquid clearance in dysfunctional lungs. This protective effect is blunted upon mutation of residues T105, E107 and E110 in human TNF into alanine or upon pre-incubation of the cytokine with the disaccharide N,N'-diacetylchitobiose. In this study, we used molecular docking and molecular dynamics simulation to predict the binding sites for N,N'-diacetylchitobiose and trimannose-O-ethyl in the lectin-like domain of TNF and in the TIP peptide. Specific sites (K98, S99, P100, Q102 and E116) in the three loops of the lectin-like domain provide specific binding for both oligosaccharides, but none of the residues crucial for anti-edema activity are involved in hydrogen bonding with oligosaccharides or are subjected to steric hindrance by them. These results thus suggest that neither chitobiose nor trimannose affect crucial amino acids, while they occupy the cavity in the lectin-like domain. Consequently, both crucial amino acids and the emptiness of the cavity in the lectin-like domain may be critical for TNF's lectin-like activity. Analogously, the R4, E5, P7, Y16 amino acids of the TIP peptide are involved in forming hydrogen bonds with both oligosaccharides, whereas residues T6, E8 and E11 (corresponding to T105, E107 and E110 in hTNF) play an important role in stabilizing the peptide-oligosaccharide complex, supporting the hypothesis that amino acids in the polar region (TPEGAE) of the TIP peptide represent only a partial binding motif for sugars.

Original languageEnglish (US)
Pages (from-to)4236-4243
Number of pages8
JournalCurrent Pharmaceutical Design
Volume18
Issue number27
DOIs
StatePublished - Sep 21 2012

Fingerprint

Oligosaccharides
Lectins
Tumor Necrosis Factor-alpha
Binding Sites
Peptides
Amino Acids
Cold Climate
Alveolar Epithelial Cells
Amiloride
Disaccharides
Molecular Dynamics Simulation
Hydrogen Bonding
Alanine
Hydrogen
Edema
Sodium
Cytokines
Lung
Mutation

Keywords

  • Alveolar liquid clearance
  • Lectin-like domain
  • Molecular docking
  • Molecular dynamics simulation
  • Oligosaccharides
  • TIP peptide
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

A computational study of the oligosaccharide binding sites in the lectin-like domain of tumor necrosis factor and the TNF-derived TIP peptide. / Dulebo, Alexander; Ettrich, Rüdiger; Lucas, Rudolf; Kaftan, David.

In: Current Pharmaceutical Design, Vol. 18, No. 27, 21.09.2012, p. 4236-4243.

Research output: Contribution to journalArticle

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