A novel inhibitor of complement C5 provides structural insights into activation
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 f...
| Egile Nagusiak: | , , , , , , , , |
|---|---|
| Formatua: | Working paper |
| Argitaratua: |
2019
|
| _version_ | 1826273982493491200 |
|---|---|
| author | Reichhardt, M Johnson, S Tang, T Morgan, T Tebeka, N Popitsch, N Deme, J Jore, M Lea, S |
| author_facet | Reichhardt, M Johnson, S Tang, T Morgan, T Tebeka, N Popitsch, N Deme, J Jore, M Lea, S |
| author_sort | Reichhardt, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:36:30Z |
| format | Working paper |
| id | oxford-uuid:5a13c1d8-2c3c-4d74-adb8-4391608c67ae |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:36:30Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:5a13c1d8-2c3c-4d74-adb8-4391608c67ae2022-03-26T17:13:38ZA novel inhibitor of complement C5 provides structural insights into activationWorking paperhttp://purl.org/coar/resource_type/c_8042uuid:5a13c1d8-2c3c-4d74-adb8-4391608c67aeSymplectic Elements at Oxford2019Reichhardt, MJohnson, STang, TMorgan, TTebeka, NPopitsch, NDeme, JJore, MLea, SAbstract 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. |
| spellingShingle | Reichhardt, M Johnson, S Tang, T Morgan, T Tebeka, N Popitsch, N Deme, J Jore, M Lea, S A novel inhibitor of complement C5 provides structural insights into activation |
| title | A novel inhibitor of complement C5 provides structural insights into activation |
| title_full | A novel inhibitor of complement C5 provides structural insights into activation |
| title_fullStr | A novel inhibitor of complement C5 provides structural insights into activation |
| title_full_unstemmed | A novel inhibitor of complement C5 provides structural insights into activation |
| title_short | A novel inhibitor of complement C5 provides structural insights into activation |
| title_sort | novel inhibitor of complement c5 provides structural insights into activation |
| work_keys_str_mv | AT reichhardtm anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT johnsons anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT tangt anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT morgant anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT tebekan anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT popitschn anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT demej anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT jorem anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT leas anovelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT reichhardtm novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT johnsons novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT tangt novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT morgant novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT tebekan novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT popitschn novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT demej novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT jorem novelinhibitorofcomplementc5providesstructuralinsightsintoactivation AT leas novelinhibitorofcomplementc5providesstructuralinsightsintoactivation |