The nitrone spin trap 5,5dimethyl1pyrroline Noxide binds to toll-like receptor-2-TIR-BB-loop domain and dampens downstream inflammatory signaling.
Biochim Biophys Acta Mol Basis Dis
; 1865(6): 1152-1159, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-30684639
ABSTRACT
The nitrone spin trap 5,5dimethyl1pyrroline Noxide (DMPO) dampens endotoxin-induced and TLR4-driven priming of macrophages, but the mechanism remains unknown. The available information suggests a direct binding of DMPO to the TIR domain, which is shared between TLRs. However, TLR2-TIR domain is the only TLR that have been crystallized. Our in silico data show that DMPO binds to four specific residues in the BB-loop within the TLR2-TIR domain. Our functional analysis using hTLR2.6-expressing HEKs cells showed that DMPO can block zymosan-triggered-TLR2-mediated NF-κB activation. However, DMPO did not affect the overall TLR2-MyD88 protein-protein interaction. DMPO binds to the BB-loop in the TIR-domain and dampens downstream signaling without affecting the overall TIR-MyD88 interaction. These data encourage the use of DMPO-derivatives as potential mechanism-based inhibitors of TLR-triggered inflammation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Marcadores de Spin
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Transdução de Sinais
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Óxidos N-Cíclicos
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Receptor 2 Toll-Like
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Inflamação
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Óxidos de Nitrogênio
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article