5FBI

COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND 3b

5FBI の概要

• エントリーDOI: 10.2210/pdb5fbi/pdb
• 分子名称: Complement factor D, GLYCEROL, 3-[(2-aminocarbonyl-1~{H}-indol-5-yl)oxymethyl]benzoic acid, ... (4 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted: P00746
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25141.52

構造登録者

Ostermann, N.,Zink, F. (登録日: 2015-12-14, 公開日: 2016-10-26, 最終更新日: 2024-10-09)

主引用文献

Maibaum, J.,Liao, S.M.,Vulpetti, A.,Ostermann, N.,Randl, S.,Rudisser, S.,Lorthiois, E.,Erbel, P.,Kinzel, B.,Kolb, F.A.,Barbieri, S.,Wagner, J.,Durand, C.,Fettis, K.,Dussauge, S.,Hughes, N.,Delgado, O.,Hommel, U.,Gould, T.,Mac Sweeney, A.,Gerhartz, B.,Cumin, F.,Flohr, S.,Schubart, A.,Jaffee, B.,Harrison, R.,Risitano, A.M.,Eder, J.,Anderson, K.
Small-molecule factor D inhibitors targeting the alternative complement pathway.
Nat.Chem.Biol., 12:1105-1110, 2016

PubMed Abstract: Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.

PubMed: 27775713
DOI: 10.1038/nchembio.2208

実験手法

X-RAY DIFFRACTION (1.47 Å)