What is it about?
We discover that a peptide made from tiny building blocks of biomolecules called amino acids can precisely lock onto a specific part of a key protein player in inflammation. By doing so, it prevents the protein from getting into its 'active mode', essentially stopping it from sending signals that cause inflammation.
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Why is it important?
Tumor necrosis factor (TNF) and its binding counterpart TNF receptor 1 (TNFR1) behave like a switch that controls inflammation—it helps the body respond to threats like infections. However, excessive TNF can lead to autoimmune and inflammatory diseases such as rheumatoid arthritis, chronic liver diseases (e.g., NAFLD/NASH), chronic kidney disease, Crohn's disease, multiple sclerosis, and Alzheimer's disease. Current TNF-blocking treatments are expensive and can have serious side effects due to them shutting down normal functions of other important proteins that interact with TNF and are responsible for maintaining the body immune system. To achieve a more precise and effective solution, we focus on targeting TNFR1 instead of blocking TNF. Our new strategy involves using a peptide, which is a tiny biomolecule, to latch onto TNFR1 and stop it from causing inflammation. By shutting down TNFR1 directly, this strategy does not interfere with the interaction between TNF and other important proteins as well as the associated biological functions. This could pave the way for safer and more effective treatments for inflammation in the future.
Perspectives
Think of 'protein conformation' like the shape or structure of a key. Just as a key needs to be in the right shape to fit into a lock, biological molecules in our body need to be in the right shape, position, or orientation to do their jobs. In this case, we have found a way to target a specific shape of a molecule involved in inflammation, almost like tweaking the key so it can't unlock the door. This therapeutic targeting strategy could be generally applied to other proteins involved in human health and diseases.
Chih Hung Lo
Nanyang Technological University
Read the Original
This page is a summary of: Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor–ligand signaling complex, Proceedings of the National Academy of Sciences, March 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2308132121.
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Resources
Conformational states of TNFR1 as a molecular switch for receptor function
Conformational states of TNFR1 as a molecular switch for receptor function
Noncompetitive inhibitors of TNFR1 probe conformational activation states
Noncompetitive inhibitors of TNFR1 probe conformational activation states
An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors
An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors
Fluorescence-Based TNFR1 Biosensor for Monitoring Receptor Structural and Conformational Dynamics and Discovery of Small Molecule Modulators
Fluorescence-Based TNFR1 Biosensor for Monitoring Receptor Structural and Conformational Dynamics and Discovery of Small Molecule Modulators
Zafirlukast Is a Promising Scaffold for Selectively Inhibiting TNFR1 Signaling
Zafirlukast Is a Promising Scaffold for Selectively Inhibiting TNFR1 Signaling
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