5wux
From Proteopedia
TNFalpha-certolizumab Fab
Structural highlights
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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
Categories: Human | Heo, Y S | Lee, J U | Antibody | Immune system