Structure of Compstatin in Complex with Complement Component C3c Reveals a New Mechanism of Complement Inhibition

Bert J.C Janssen,Els F Halff,John D Lambris,Piet Gros

doi:10.1074/jbc.m704587200

Bert J.C Janssen, Els F Halff + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m704587200

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Abstract

Undesired complement activation is a major cause of tissue injury in various pathological conditions and contributes to several immune complex diseases. Compstatin, a 13-residue peptide, is an effective inhibitor of the activation of complement component C3 and thus blocks a central and crucial step in the complement cascade. The precise binding site on C3, the structure in the bound form, and the exact mode of action of compstatin are unknown. Here we present the crystal structure of compstatin in complex with C3c, a major proteolytic fragment of C3. The structure reveals that the compstatin-binding site is formed by the macroglobulin (MG) domains 4 and 5. This binding site is part of the structurally stable MG-ring formed by domains MG 1-6 and is far away from any other known binding site on C3. Compstatin does not alter the conformation of C3c, whereas compstatin itself undergoes a large conformational change upon binding. We propose a model in which compstatin sterically hinders the access of the substrate C3 to the convertase complexes, thus blocking complement activation and amplification. These insights are instrumental for further development of compstatin as a potential therapeutic.

Highlights

Proteolytic activation of C3 yields C3b, which covalently binds to pathogenic or self surfaces, providing a strong signal for clearance of the tagged particles. Because compstatin blocks this critical step of complement activation and because it is a small non-immunogenic peptide, compstatin has the potential to be developed into a therapeutic agent
Mutational studies showed that the polar ␤-turn and the hydrophobic cluster are essential for the inhibitory activity of compstatin (10 –13)
Using the available structural data, we propose a model for the inhibitory activity of compstatin in blocking substrate C3 binding to C3 convertases

Summary

The abbreviations used are

C3, complement component 3; MG, macroglobulin; CRIg, complement receptor of the immunoglobulin superfamily; r.m.s., root mean square. Soulika et al [17] showed that the binding site resides in the 40-kDa C-terminal part of the ␤-chain that is common to these proteins. Overall, these and other studies have lead to a model in which compstatin inhibits complement activation by blocking binding of C3 to the C3 convertases, either through inducing a conformational change in C3 or through causing steric hindrance when bound to C3 [11, 17]. Using the available structural data, we propose a model for the inhibitory activity of compstatin in blocking substrate C3 binding to C3 convertases

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DISCUSSION