4D9Q

Inhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor D

4D9Q の概要

• エントリーDOI: 10.2210/pdb4d9q/pdb
• 関連するPDBエントリー: 4D9R
• 分子名称: Factor D, Anti-Factor D, light chain, Anti-Factor D, heavy chain, ... (7 entities in total)
• 機能のキーワード: factor d, complement, antibody, exosite, fab, chymotrypsin, protease, hydrolase-immune system complex, hydrolase/immune system
• 由来する生物種: Macaca mulatta (rhesus macaque,rhesus macaques,rhesus monkeys); 詳細
• 細胞内の位置: Secreted : P01857
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 143365.77

構造登録者

Murray, J.M.,Wiesmann, C. (登録日: 2012-01-11, 公開日: 2012-02-22, 最終更新日: 2024-10-09)

主引用文献

Katschke, K.J.,Wu, P.,Ganesan, R.,Kelley, R.F.,Mathieu, M.A.,Hass, P.E.,Murray, J.,Kirchhofer, D.,Wiesmann, C.,van Lookeren Campagne, M.
Inhibiting alternative pathway complement activation by targeting the factor d exosite.
J.Biol.Chem., 287:12886-12892, 2012

PubMed Abstract: By virtue of its amplifying property, the alternative complement pathway has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macromolecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of the substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 and 2.3 Å, respectively) revealed the molecular details of the inhibitory mechanism. The structures show that the AFD-binding site includes surface loops of FD that form part of the FD exosite. Thus, AFD inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway.

PubMed: 22362762
DOI: 10.1074/jbc.M112.345082

実験手法

X-RAY DIFFRACTION (2.28 Å)