7ta3
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Trimer-to-Monomer Disruption of Tumor Necrosis Factor-alpha (TNF-alpha) by alpha-peptide-3== | |
| + | <StructureSection load='7ta3' size='340' side='right'caption='[[7ta3]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7ta3]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TA3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ta3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ta3 OCA], [https://pdbe.org/7ta3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ta3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ta3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ta3 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/TNFA_HUMAN TNFA_HUMAN] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:[https://omim.org/entry/607507 607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). | ||
| + | == 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 7ta3" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Synthetic construct]] | ||
| + | [[Category: Bingman CA]] | ||
| + | [[Category: Gellman SH]] | ||
| + | [[Category: Niu J]] | ||
Current revision
Trimer-to-Monomer Disruption of Tumor Necrosis Factor-alpha (TNF-alpha) by alpha-peptide-3
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