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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.<ref>PMID:16829952</ref>  The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.<ref>PMID:16829952</ref>  
[https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.<ref>PMID:16829952</ref>  The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.<ref>PMID:16829952</ref>  
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== Publication Abstract from PubMed ==
Aberrant tumor necrosis factor-alpha (TNFalpha) signaling is associated with many inflammatory diseases. The homotrimeric quaternary structure of TNFalpha is essential for receptor recognition and signal transduction. Previously, we described an engineered alpha/beta-peptide inhibitor that potently suppresses TNFalpha activity and resists proteolysis. Here, we present structural evidence that both the alpha/beta-peptide inhibitor and an all-alpha analogue bind to a monomeric form of TNFalpha. Calorimetry data support a 1:1 inhibitor/TNFalpha stoichiometry in solution. In contrast, previous cocrystal structures involving peptide or small-molecule inhibitors have shown the antagonists engaging a TNFalpha dimer. The structural data reveal why our inhibitors favor monomeric TNFalpha. Previous efforts to block TNFalpha-induced cell death with peptide inhibitors revealed that surfactant additives to the assay conditions cause a more rapid manifestation of inhibitory activity than is observed in the absence of additives. We attributed this effect to a loose surfactant TNFalpha association that lowers the barrier to trimer dissociation. Here, we used the new structural data to design peptide inhibitors bearing a surfactant-inspired appendage intended to facilitate TNFalpha trimer dissociation. The appendage modified the time course of protection from cell death.


Trimer-to-Monomer Disruption Mechanism for a Potent, Protease-Resistant Antagonist of Tumor Necrosis Factor-alpha Signaling.,Niu J, Cederstrand AJ, Eddinger GA, Yin B, Checco JW, Bingman CA, Outlaw VK, Gellman SH J Am Chem Soc. 2022 Jun 8;144(22):9610-9617. doi: 10.1021/jacs.1c13717. Epub 2022 , May 25. PMID:35613436<ref>PMID:35613436</ref>
==See Also==
 
*[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
== References ==
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Latest revision as of 07:21, 3 April 2024

Trimer-to-Monomer Disruption of Tumor Necrosis Factor-alpha (TNF-alpha) by unnatural alpha/beta-peptide-1

7ta6, resolution 2.67Å

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