4D9R

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

Summary for 4D9R

• Entry DOI: 10.2210/pdb4d9r/pdb
• Related: 4D9Q
• Descriptor: Complement factor D, Fab light chain, Fab heavy chain, ... (5 entities in total)
• Functional Keywords: factor d, complement, antibody, exosite, fab, chymotrypsin, protease, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00746 P01834 P01857
• Total number of polymer chains: 6
• Total formula weight: 141799.75

Authors

Murray, J.M.,Wiesmann, C. (deposition date: 2012-01-11, release date: 2012-02-22, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.42 Å)