Crystal structure of TNFalpha in complex with Adalimumab Fab fragment
[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).
[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
TNFalpha-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNFalpha and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared with Etanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNFalpha and functions as a TNFalpha receptor-binding blocker. To further elucidate the variations between TNFalpha inhibitors, we solved the crystal structure of TNFalpha in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNFalpha and revealed the mechanism of Adalimumab inhibition of TNFalpha by occupying the TNFalpha receptor-binding site. The larger antigen-antibody interface in TNFalpha Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab.
Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor alpha-associated diseases from a molecular view.,Hu S, Liang S, Guo H, Zhang D, Li H, Wang X, Yang W, Qian W, Hou S, Wang H, Guo Y, Lou Z J Biol Chem. 2013 Sep 20;288(38):27059-67. doi: 10.1074/jbc.M113.491530. Epub, 2013 Aug 13. PMID:23943614
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