7ta3

Trimer-to-Monomer Disruption of Tumor Necrosis Factor-alpha (TNF-alpha) by alpha-peptide-3

spinqualitylabelsall models 7ta3, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ta3 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TNFA_HUMAN Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM: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 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. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tumor necrosis factor 3D structures

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