5YOY

Crystal structure of the human tumor necrosis factor in complex with golimumab Fv

5YOY の概要

• エントリーDOI: 10.2210/pdb5yoy/pdb
• 分子名称: Tumor necrosis factor, Golimumab light chain variable region, Golimumab heavy chain variable region, ... (4 entities in total)
• 機能のキーワード: cytokine, antibody, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 18
• 化学式量合計: 279323.32

構造登録者

Ono, M.,Horita, S.,Sato, Y.,Nomura, Y.,Iwata, S.,Nomura, N. (登録日: 2017-10-31, 公開日: 2018-05-09, 最終更新日: 2024-11-06)

主引用文献

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., 27:1038-1046, 2018

PubMed Abstract: Tumor necrosis factor α (TNFα) is a proinflammatory cytokine, and elevated levels of TNFα in serum are associated with various autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis, and systemic lupus erythaematosus. TNFα 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 TNFα signaling have been shown to be effective in suppressing such harmful inflammatory conditions. Golimumab (Simponi®) is an FDA-approved fully human monoclonal antibody targeting TNFα 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 TNFα at a resolution of 2.73 Å. The resolved structure reveals that golimumab binds to a distinct epitope on TNFα that does not overlap with the binding residues of TNFR2. Golimumab exerts its inhibitory effect by preventing binding of TNFR1 and TNFR2 to TNFα by steric hindrance. Golimumab does not induce conformational changes in TNFα that could affect receptor binding. This mode of action is specific to golimumab among the four anti-TNFα therapeutic antibodies currently approved for clinical use.

PubMed: 29575262
DOI: 10.1002/pro.3407

実験手法

X-RAY DIFFRACTION (2.727 Å)