 |
PDBsum entry 4xz1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
4xz1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Modification by covalent reaction or oxidation of cysteine residues in the tandem-Sh2 domains of zap-70 and syk can block phosphopeptide binding.
|
|
|
Authors
|
|
P.R.Visperas,
J.A.Winger,
T.M.Horton,
N.H.Shah,
D.J.Aum,
A.Tao,
T.Barros,
Q.Yan,
C.G.Wilson,
M.R.Arkin,
A.Weiss,
J.Kuriyan.
|
|
|
Ref.
|
|
Biochem J, 2015,
465,
149-161.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase
(Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell
antigen receptor signalling respectively. They are recruited, via their
tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated
immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of
immune antigen receptors. Because of their critical roles in immune signalling,
ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases.
We show that three thiol-reactive small molecules can prevent the tandem-SH2
domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a
specific cysteine residue in the phosphotyrosine-binding pocket of each protein
(Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of
these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive
to the presence of H2O2 and these two cysteine residues are also necessary for
inhibition by H2O2. Our findings suggest a mechanism by which the reactive
oxygen species generated during responses to antigen could attenuate signalling
through these kinases and may also inform the development of ZAP-70 and Syk
inhibitors that bind covalently to their SH2 domains.
|
|
|
|
|
|
|
