5FBE

COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND2

Summary for 5FBE

• Entry DOI: 10.2210/pdb5fbe/pdb
• Descriptor: Complement factor D, GLYCEROL, methyl 2-[[[(2~{S})-2-[[3-(trifluoromethyloxy)phenyl]carbamoyl]pyrrolidin-1-yl]carbonylamino]methyl]benzoate, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P00746
• Total number of polymer chains: 1
• Total formula weight: 25296.64

Authors

Ostermann, N.,Zink, F. (deposition date: 2015-12-14, release date: 2016-10-26, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.43 Å)