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Nat Struct Mol Biol. 2016 May;23(5):378-86. doi: 10.1038/nsmb.3196. Epub 2016 Mar 28.

Structural basis for therapeutic inhibition of complement C5.

Author information

1
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
2
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
3
Centre for Ecology and Hydrology, Wallingford, UK.
4
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
5
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Victoria, Australia.

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.

PMID:
27018802
PMCID:
PMC5771465
DOI:
10.1038/nsmb.3196
[Indexed for MEDLINE]
Free PMC Article

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