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Structure of and influence of a tick complement inhibitor on human complement component 5

Nature Immunology volume 9, pages 753–760 (2008)Cite this article

An Erratum to this article was published on 01 August 2008

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Abstract

To provide insight into the structural and functional properties of human complement component 5 (C5), we determined its crystal structure at a resolution of 3.1 Å. The core of C5 adopted a structure resembling that of C3, with the domain arrangement at the position corresponding to the C3 thioester being very well conserved. However, in contrast to C3, the convertase cleavage site in C5 was ordered and the C345C domain flexibly attached to the core of C5. Binding of the tick C5 inhibitor OmCI to C5 resulted in stabilization of the global conformation of C5 but did not block the convertase cleavage site. The structure of C5 may render possible a structure-based approach for the design of new selective complement inhibitors.

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Figure 1: The structure of human C5.
Figure 2: The C5d-MG8 domain interfaces in C5 and the corresponding interface in C3 and TEP.
Figure 3: The C5a anaphylatoxin in C5.
Figure 4: Conserved surface areas of C5.
Figure 5: Solution structure of C5.

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  • 20 June 2008

    In the version of this article initially published, the numbers in the “Rsym” row in Table 1 are in the wrong columns. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank L. Kristensen for technical assistance; C. Andersen for help with figures; the staff of Elettra, Max-lab, the European Synchrotron Radiation Facility, and the Swiss Light Source for help with data collection; R. Ogata (Torrey Pines Institute for Molecular Studies) for C5-C345C; and P. Morgan (Cardiff University) for polyclonal rabbit antibody to OmCI IgG. Supported by the Danish Natural Science Research Council, the Novo Nordisk Foundation, the Carlsberg Foundation, the Danish National Research Foundation and Dansync (G.R.A., L.J., J.S.P. and L.S.-J.); and by the British Biotechnology and Biological Sciences Research Council and the National Environmental Research Council (S.M.L., P.R. and M.A.N.).

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Author notes

  1. Lasse Jenner

    Present address: Present address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67404, France.,

Authors and Affiliations

  1. Department of Molecular Biology, University of Aarhus, Aarhus, DK-8000, Denmark

    Folmer Fredslund, Nick S Laursen, Lasse Jenner, Lars Sottrup-Jensen & Gregers R Andersen

  2. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3ER, UK

    Pietro Roversi & Susan M Lea

  3. Department of Chemistry, University of Aarhus, Aarhus, DK-8000, Denmark

    Cristiano L P Oliveira & Jan S Pedersen

  4. Centre for mRNP Biogenesis and Metabolism, University of Aarhus, Denmark

    Cristiano L P Oliveira, Jan S Pedersen & Gregers R Andersen

  5. Centre for Ecology and Hydrology Oxford, Oxford, OX1 3SR, UK

    Miles A Nunn

  6. La Jolla Institute for Experimental Medicine, 505 Coast Boulevard S., La Jolla, 92037, California, USA

    Richard Discipio

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Contributions

F.F., crystallization, data collection, structure determination, refinement and analysis, and manuscript preparation; N.S.L. and L.S.-J., purification and analysis of C5 and C5-OmCI; P.R. and S.M.L., experimental phasing and molecular replacement; M.A.N., surface plasmon resonance experiments and preparation of OmCI; C.L.P.O. and J.S.P., SAXS analysis; L.J. and R.D., initial protein purification, crystallization and data collection; and G.R.A., conceptual design, structure analysis and manuscript preparation.

Corresponding author

Correspondence to Gregers R Andersen.

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Fredslund, F., Laursen, N., Roversi, P. et al. Structure of and influence of a tick complement inhibitor on human complement component 5. Nat Immunol 9, 753–760 (2008). https://doi.org/10.1038/ni.1625

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