Structural basis for therapeutic inhibition of complement C5

Matthijs M Jore, Steven Johnson, Devon Sheppard, Natalie M Barber, Yang I Li, Miles A Nunn, Hans Elmlund, Susan M Lea

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by eculizumab, one of the world s most expensive drugs. However, the mechanism of C5 activation by C5 convertases remains elusive, thus limiting development of therapeutics. Here we identify and characterize a new protein family of tick-derived C5 inhibitors. Structures of C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI, or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent activation of C5. The positions of the inhibitor-binding sites and the ability of all three C5-inhibitor complexes to competitively inhibit the C5 convertase conflict with earlier steric-inhibition models, thus suggesting that a priming event is needed for activation.
Original languageEnglish
Pages (from-to)378-386
Number of pages9
JournalNature Structural and Molecular Biology
Volume23
Issue number5
DOIs
Publication statusPublished - May 2016

Keywords

  • electron microscopy
  • immunology
  • NMR spectroscopy
  • proteins
  • x-ray crystallography

Cite this

Jore, M. M., Johnson, S., Sheppard, D., Barber, N. M., Li, Y. I., Nunn, M. A., ... Lea, S. M. (2016). Structural basis for therapeutic inhibition of complement C5. Nature Structural and Molecular Biology, 23(5), 378-386. https://doi.org/10.1038/nsmb.3196
Jore, Matthijs M ; Johnson, Steven ; Sheppard, Devon ; Barber, Natalie M ; Li, Yang I ; Nunn, Miles A ; Elmlund, Hans ; Lea, Susan M. / Structural basis for therapeutic inhibition of complement C5. In: Nature Structural and Molecular Biology. 2016 ; Vol. 23, No. 5. pp. 378-386.
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Jore, MM, Johnson, S, Sheppard, D, Barber, NM, Li, YI, Nunn, MA, Elmlund, H & Lea, SM 2016, 'Structural basis for therapeutic inhibition of complement C5' Nature Structural and Molecular Biology, vol. 23, no. 5, pp. 378-386. https://doi.org/10.1038/nsmb.3196

Structural basis for therapeutic inhibition of complement C5. / Jore, Matthijs M; Johnson, Steven; Sheppard, Devon; Barber, Natalie M; Li, Yang I; Nunn, Miles A; Elmlund, Hans; Lea, Susan M.

In: Nature Structural and Molecular Biology, Vol. 23, No. 5, 05.2016, p. 378-386.

Research output: Contribution to journalArticleResearchpeer-review

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Jore MM, Johnson S, Sheppard D, Barber NM, Li YI, Nunn MA et al. Structural basis for therapeutic inhibition of complement C5. Nature Structural and Molecular Biology. 2016 May;23(5):378-386. https://doi.org/10.1038/nsmb.3196