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Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2009 Apr 17; Vol. 284 (16), pp. 10473-9. Date of Electronic Publication: 2009 Feb 05. - Publication Year :
- 2009
-
Abstract
- Amplification of the complement cascade through the alternative pathway can lead to excessive inflammation. Targeting C3b, a component central to the alternative pathway of complement, provides a powerful approach to inhibit complement-mediated immune responses and tissue injury. In the present study, phage display technology was employed to generate an antibody that selectively recognizes C3b but not the non-activated molecule C3. The crystal structure of C3b in complex with a Fab fragment of this antibody (S77) illustrates the structural basis for this selectivity. Cleavage of C3 to C3b results in a plethora of structural changes within C3, including the rearrangement of macroglobulin domain 6 enabling binding of S77 to the adjacent macroglobulin domain 7 domain. S77 blocks binding of factor B to C3b inhibiting the first step in the formation of the alternative pathway C3 convertase. In addition, S77 inhibits C5 binding to C3b. This results in significantly reduced formations of anaphylatoxins and membrane-attack complexes. This study for the first time demonstrates the structural basis for complement inhibition by a C3b-selective antibody and provides insights into the molecular mechanisms of alternative pathway complement activation.
- Subjects :
- Animals
Complement C3 Convertase, Alternative Pathway metabolism
Complement C3b chemistry
Complement C3b genetics
Complement C3b metabolism
Complement C5 Convertase, Alternative Pathway metabolism
Crystallography, X-Ray
Enzyme Inhibitors chemistry
Enzyme Inhibitors metabolism
Enzyme Stability
Humans
Macaca mulatta
Models, Molecular
Molecular Sequence Data
Peptide Library
Peptides, Cyclic chemistry
Peptides, Cyclic metabolism
Receptors, Complement 3b chemistry
Receptors, Complement 3b metabolism
Antibodies chemistry
Antibodies metabolism
Complement C3b immunology
Complement Pathway, Alternative physiology
Immunoglobulin Fab Fragments chemistry
Immunoglobulin Fab Fragments metabolism
Protein Conformation
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 284
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19196712
- Full Text :
- https://doi.org/10.1074/jbc.M809106200