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-Structure paper
Title | An inhibitor of complement C5 provides structural insights into activation. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 117, Issue 1, Page 362-370, Year 2020 |
Publish date | Jan 7, 2020 |
Authors | Martin P Reichhardt / Steven Johnson / Terence Tang / Thomas Morgan / Nchimunya Tebeka / Niko Popitsch / Justin C Deme / Matthijs M Jore / Susan M Lea / |
PubMed Abstract | The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick lasts for days, and the tick must therefore rely on inhibitors to counter ...The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick 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. |
External links | Proc Natl Acad Sci U S A / PubMed:31871188 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.7 - 3.5 Å |
Structure data | EMDB-4983, PDB-6rqj: PDB-6rpt: |
Chemicals | ChemComp-GOL: ChemComp-HOH: |
Source |
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Keywords | IMMUNOSUPPRESSANT / complement / inhibitor / innate immunity / inflammation / C5 / terminal pathway inhibitor |