Structure-guided engineering of tick evasins for targeting chemokines in inflammatory diseases.
Proc Natl Acad Sci U S A
; 119(9)2022 03 01.
Article
em En
| MEDLINE
| ID: mdl-35217625
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carrapatos
/
Engenharia de Proteínas
/
Quimiocinas
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Proteínas de Artrópodes
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Inflamação
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article