| Autor: |
Ram Prasad Bhusal, Pramod Aryal, Shankar Raj Devkota, Rina Pokhrel, Menachem J. Gunzburg, Simon R. Foster, Herman D. Lim, Richard J. Payne, Matthew C. J. Wilce, Martin J. Stone |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America. 119(9) |
| ISSN: |
1091-6490 |
| Popis: |
As natural chemokine inhibitors, evasin proteins produced in tick saliva are potential therapeutic agents for numerous inflammatory diseases. Engineering evasins to block the desired chemokines and avoid off-target side effects requires structural understanding of their target selectivity. Structures of the class A evasin EVA-P974 bound to human CC chemokine ligands 7 and 17 (CCL7 and CCL17) and to a CCL8-CCL7 chimera reveal that the specificity of class A evasins for chemokines of the CC subfamily is defined by conserved, rigid backbone-backbone interactions, whereas the preference for a subset of CC chemokines is controlled by side-chain interactions at four hotspots in flexible structural elements. Hotspot mutations alter target preference, enabling inhibition of selected chemokines. The structure of an engineered EVA-P974 bound to CCL2 reveals an underlying molecular mechanism of EVA-P974 target preference. These results provide a structure-based framework for engineering evasins as targeted antiinflammatory therapeutics. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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