Small molecule AX-024 reduces T cell proliferation independently of CD3ϵ/Nck1 interaction, which is governed by a domain swap in the Nck1-SH3.1 domain.
T-cell receptor (TCR)
adaptor protein
analytical ultracentrifugation
cell proliferation
crystal structure
nuclear magnetic resonance (NMR)
protein drug interaction
protein structure
structure-function
surface plasmon resonance (SPR)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
05 06 2020
05 06 2020
Historique:
received:
05
02
2020
revised:
15
04
2020
pubmed:
23
4
2020
medline:
29
12
2020
entrez:
23
4
2020
Statut:
ppublish
Résumé
Activation of the T cell receptor (TCR) results in binding of the adapter protein Nck (noncatalytic region of tyrosine kinase) to the CD3ϵ subunit of the TCR. The interaction was suggested to be important for the amplification of TCR signals and is governed by a proline-rich sequence (PRS) in CD3ϵ that binds to the first Src homology 3 (SH3) domain of Nck (Nck-SH3.1). Inhibition of this protein/protein interaction ameliorated inflammatory symptoms in mouse models of multiple sclerosis, psoriasis, and asthma. A small molecule, AX-024, was reported to inhibit the Nck/CD3ϵ interaction by physically binding to the Nck1-SH3.1 domain, suggesting a route to develop an inhibitor of the Nck1/CD3ϵ interaction for modulating TCR activity in autoimmune and inflammatory diseases. We show here that AX-024 reduces T cell proliferation upon weak TCR stimulation but does not significantly affect phosphorylation of Zap70 (ζ chain of T cell receptor-associated protein kinase 70). We also find that AX-024 is likely not involved in modulating the Nck/TCR interaction but probably has other targets in T cells. An array of biophysical techniques did not detect a direct interaction between AX-024 and Nck-SH3.1
Identifiants
pubmed: 32317279
pii: S0021-9258(17)49428-2
doi: 10.1074/jbc.RA120.012788
pmc: PMC7278359
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CD3 Complex
0
Nck protein
0
Oncogene Proteins
0
Small Molecule Libraries
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7849-7864Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 Richter et al.
Déclaration de conflit d'intérêts
The authors declare that they have no conflicts of interest with the contents of this article.
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