Structural highlights
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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.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2]
Publication Abstract from PubMed
A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor alpha (TNFalpha). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFalpha that inhibits the protein-protein interaction between TNFalpha and TNFalpha receptors. SPD-304 may employ a similar mechanism of inhibition.
Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction.,Blevitt JM, Hack MD, Herman KL, Jackson PF, Krawczuk PJ, Lebsack AD, Liu AX, Mirzadegan T, Nelen MI, Patrick AN, Steinbacher S, Milla ME, Lumb KJ J Med Chem. 2017 Mar 16. PMID:28300404[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
- ↑ Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
- ↑ Blevitt JM, Hack MD, Herman KL, Jackson PF, Krawczuk PJ, Lebsack AD, Liu AX, Mirzadegan T, Nelen MI, Patrick AN, Steinbacher S, Milla ME, Lumb KJ. Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction. J Med Chem. 2017 Mar 16. PMID:28300404
