Letter | Published:

Structure of C3b reveals conformational changes that underlie complement activity

Nature volume 444, pages 213216 (09 November 2006) | Download Citation



Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity1,2. Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces3 to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions4. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-Å resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 Å away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the α-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.

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We acknowledge the European Synchrotron Radiation Facility for provision of synchrotron radiation facilities; and S.J. Kolodziej and J.K. Stoops (Houston) for providing the native α2-macroglobulin and methylamine-treated α2-macroglobulin EM-reconstruction maps. We thank B. Nilsson (Uppsala), R.B.G. Ravelli (Grenoble) and E.G. Huizinga (Utrecht) for reading the manuscript. This work was supported by a ‘Pioneer’ programme grant to P.G. by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) and an NIH grant to J.D.L.

Author information


  1. Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

    • Bert J. C. Janssen
    •  & Piet Gros
  2. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia 19104, USA

    • Agni Christodoulidou
    •  & John D. Lambris
  3. European Molecular Biology Laboratory, Grenoble Outstation, 38042 Grenoble, Cedex 9, France

    • Andrew McCarthy


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Competing interests

Coordinates and structure factors of the C3b structure have been deposited in the Protein Data Bank with accession number 2I07. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Piet Gros.

Supplementary information

Word documents

  1. 1.

    Supplementary Figure

    Figure captions for Supplementary Tables 1 and 2, Supplementary Figures 1 to 3 and Supplementary Movie.

PDF files

  1. 1.

    Supplementary Table 1

    Diffraction data, refinement statistics and molecular replacement scores for C3b

  2. 2.

    Supplementary Table 2

    Domain rotation and translation between C3b, C3 and C3c.

  3. 3.

    Supplementary Figure 1

    Electron density for the individual domains of C3b.

  4. 4.

    Supplementary Figure 2

    Proteolytic cleavage sites of factor I mapped on the structure of C3b.

  5. 5.

    Supplementary Figure 3

    Modeling of native and methylamine 2-macroglobulin based on 25-Å resolution EM reconstruction maps.


  1. 1.

    Supplementary Movie

    Conformational transition of C3 into C3b.

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