4d9q
Inhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor DInhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor D
Structural highlights
FunctionPublication Abstract from PubMedThe alternative complement pathway, by virtue of its amplifying property, 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 macro-molecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 A and 2.3 A, respectively) revealed the molecular details of the inhibitory mechanism. The structures showed that the AFD binding site included surface loops of FD that form part of the C3bB exosite. Thus, AFD inhibited 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. Inhibiting alternative pathway complement activation by targeting the exosite of factor D.,Katschke KJ, Wu P, Ganesan R, Kelley RF, Mathieu MA, Hass PE, Murray J, Kirchhofer D, Wiesmann C, van Lookeren Campagne M J Biol Chem. 2012 Feb 23. PMID:22362762[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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