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J. Biol. Chem., Vol. 282, Issue 40, 29241-29247, October 5, 2007

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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. Lambris¹, and Piet Gros²

From the Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands and the Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

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.

Received for publication, June 4, 2007 , and in revised form, July 25, 2007.

^* This work was supported by "Pionier" program Grant 700.99.402 (to P. G.) by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) and by National Institutes of Health Grants GM069736, GM62134, and AI30040 (to J. D. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2QKI) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains two supplemental tables and two supplemental figures as well as additional references.

¹ To whom correspondence may be addressed. E-mail: lambris{at}mail.med.upenn.edu. ²To whom correspondence may be addressed: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Tel.: 31-30-2533127; Fax: 31-30-2533940; E-mail: p.gros{at}chem.uu.nl.

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