Structural highlights
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
Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine, and elevated levels of TNFalpha in serum are associated with various autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis, and systemic lupus erythaematosus. TNFalpha performs its pleiotropic functions by binding to two structurally distinct transmembrane receptors, TNF receptor (TNFR) 1 and TNFR2. Antibody-based therapeutic strategies that block excessive TNFalpha signaling have been shown to be effective in suppressing such harmful inflammatory conditions. Golimumab (Simponi(R)) is an FDA-approved fully human monoclonal antibody targeting TNFalpha that has been widely used for the treatment of RA, AS, and CD. However, the structural basis underlying the inhibitory action of golimumab remains unclear. Here, we report the crystal structure of the Fv fragment of golimumab in complex with TNFalpha at a resolution of 2.73 A. The resolved structure reveals that golimumab binds to a distinct epitope on TNFalpha that does not overlap with the binding residues of TNFR2. Golimumab exerts its inhibitory effect by preventing binding of TNFR1 and TNFR2 to TNFalpha by steric hindrance. Golimumab does not induce conformational changes in TNFalpha that could affect receptor binding. This mode of action is specific to golimumab among the four anti-TNFalpha therapeutic antibodies currently approved for clinical use.
Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab.,Ono M, Horita S, Sato Y, Nomura Y, Iwata S, Nomura N Protein Sci. 2018 Mar 25. doi: 10.1002/pro.3407. PMID:29575262[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
- ↑ Ono M, Horita S, Sato Y, Nomura Y, Iwata S, Nomura N. Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab. Protein Sci. 2018 Mar 25. doi: 10.1002/pro.3407. PMID:29575262 doi:http://dx.doi.org/10.1002/pro.3407
