5wux
TNFalpha-certolizumab FabTNFalpha-certolizumab Fab
Structural highlights
DiseaseTNFA_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). FunctionTNFA_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 PubMedMonoclonal antibodies against TNFalpha, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFalpha, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFalpha in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFalpha by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFalpha trimer. Additionally, the DE loop and the GH loop of TNFalpha play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFalpha. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFalpha-receptor interaction. A comprehensive comparison of the interactions of TNFalpha blockers with TNFalpha revealed the epitope diversity on the surface of TNFalpha, providing a better understanding of the molecular mechanism of TNFalpha blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFalpha. Molecular Basis for the Neutralization of Tumor Necrosis Factor alpha by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases.,Lee JU, Shin W, Son JY, Yoo KY, Heo YS Int J Mol Sci. 2017 Jan 23;18(1). pii: E228. doi: 10.3390/ijms18010228. PMID:28124979[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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