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.
Keywords: lectin-like domain, tumor necrosis factor, TIP peptide, oligosaccharides, molecular docking, molecular dynamics simulation, alveolar liquid clearance, sodium uptake, amino acids, sugars.
Current Pharmaceutical Design
Title:A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide
Volume: 18 Issue: 27
Author(s): Alexander Dulebo, Rudiger Ettrich, Rudolf Lucas and David Kaftan
Affiliation:
Keywords: lectin-like domain, tumor necrosis factor, TIP peptide, oligosaccharides, molecular docking, molecular dynamics simulation, alveolar liquid clearance, sodium uptake, amino acids, sugars.
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.
Export Options
About this article
Cite this article as:
Dulebo Alexander, Ettrich Rudiger, Lucas Rudolf and Kaftan David, A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide, Current Pharmaceutical Design 2012; 18 (27) . https://dx.doi.org/10.2174/138161212802430549
DOI https://dx.doi.org/10.2174/138161212802430549 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Diagnosis of Drug-Induced Liver Disease
Current Clinical Pharmacology Alzheimers Disease and Intelligence
Current Alzheimer Research Bridging the Gap: The Potential Role of Corticosteroid Binding Globulin in Cardiac Steroid Facilitation
Current Drug Targets Alzheimer Disease and Type 2 Diabetes Mellitus: The Link to Tyrosine Hydroxylase and Probable Nutritional Strategies
CNS & Neurological Disorders - Drug Targets Hypertension, Cognitive Impairment and Dementia: An Epidemiological Perspective
Current Hypertension Reviews Triglycerides and Vascular Risk: Insights from Epidemiological Data and Interventional Studies
Current Drug Targets Angiogenesis and the Heart
Recent Patents on Cardiovascular Drug Discovery Polyphenols from Red Wine Modulate Immune Responsiveness: Biological and Clinical Significance
Current Pharmaceutical Design Therapeutic Potential of Plant Extracts and Phytochemicals Against Brain Ischemia-Reperfusion Injury: A Review
The Natural Products Journal Cysteine Proteinases of Trypanosome Parasites Novel Targets for Chemotherapy
Current Drug Targets Pyridines and Imidazopyridines with Medicinal Significance
Current Topics in Medicinal Chemistry Heart Failure in Acute Ischemic Stroke
Current Cardiology Reviews Alterations of the Kidney Cortex Proteome in Response to Exercise Training in Normoglycemic and Hyperglycemic Conditions
Current Topics in Medicinal Chemistry Dasabuvir: A Non-Nucleoside Inhibitor of NS5B for the Treatment of Hepatitis C Virus Infection
Reviews on Recent Clinical Trials Targeting CSC-Related miRNAs for Cancer Therapy by Natural Agents
Current Drug Targets Update on Medical and Surgical Management of Intracerebral Hemorrhage
Reviews on Recent Clinical Trials An Insight of Novel Pharmacological Therapies in Hypertrophic Cardiomyopathy
Medicinal Chemistry Adjunctive Therapies in Severe Pneumonia in Critical Care Patients
Infectious Disorders - Drug Targets Maternal Sepsis: Current Approaches to Recognition and Clinical Management
Current Women`s Health Reviews Renal Protective Effect of Metabolic Therapy in Patients with Coronary Artery Disease and Diabetes: From Bench to Bed Side
Current Pharmaceutical Design