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A novel inhibitor of complement C5 provides structural insights into activation

Martin P. Reichhardt, Steven Johnson, Terence Tang, Thomas Morgan, Nchimunya Tebeka, Niko Popitsch, Justin C. Deme, Matthijs M. Jore, View ORCID ProfileSusan M. Lea
doi: https://doi.org/10.1101/647354
Martin P. Reichhardt
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Steven Johnson
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Terence Tang
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Thomas Morgan
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Nchimunya Tebeka
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Niko Popitsch
2Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
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Justin C. Deme
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
3Central Oxford Structural Molecular Imaging Centre, University of Oxford, Oxford, UK
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Matthijs M. Jore
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
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Susan M. Lea
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
3Central Oxford Structural Molecular Imaging Centre, University of Oxford, Oxford, UK
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  • ORCID record for Susan M. Lea
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Abstract

The complement system is a crucial part of innate immune defences against invading pathogens. The blood-meal of the tick Rhipicephalus pulchellus lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a novel class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5-CirpT complex by cryo-electron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4-CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the novel fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a novel mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 10, 2019.
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A novel inhibitor of complement C5 provides structural insights into activation
Martin P. Reichhardt, Steven Johnson, Terence Tang, Thomas Morgan, Nchimunya Tebeka, Niko Popitsch, Justin C. Deme, Matthijs M. Jore, Susan M. Lea
bioRxiv 647354; doi: https://doi.org/10.1101/647354
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A novel inhibitor of complement C5 provides structural insights into activation
Martin P. Reichhardt, Steven Johnson, Terence Tang, Thomas Morgan, Nchimunya Tebeka, Niko Popitsch, Justin C. Deme, Matthijs M. Jore, Susan M. Lea
bioRxiv 647354; doi: https://doi.org/10.1101/647354

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