An inhibitor of complement C5 provides structural insights into activation.

Autor:	Reichhardt MP; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Johnson S; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Tang T; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Morgan T; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Tebeka N; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Popitsch N; Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, United Kingdom., Deme JC; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom.; Central Oxford Structural Molecular Imaging Centre, University of Oxford, OX1 3RE Oxford, United Kingdom., Jore MM; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom., Lea SM; Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom; susan.lea@path.ox.ac.uk.; Central Oxford Structural Molecular Imaging Centre, University of Oxford, OX1 3RE Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jan 07; Vol. 117 (1), pp. 362-370. Date of Electronic Publication: 2019 Dec 23.
DOI:	10.1073/pnas.1909973116
Abstrakt:	The complement system is a crucial part of innate immune defenses 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 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 cryoelectron 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 fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway. Competing Interests: Competing interest statement: M.M.J. and S.M.L. are authors on a patent applied for that describes members of the inhibitor family as potential protein therapeutics. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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