4XZ0

ZAP-70-tSH2:compound-A complex

Summary for 4XZ0

• Entry DOI: 10.2210/pdb4xz0/pdb
• Related: 4XZ1
• Descriptor: Tyrosine-protein kinase ZAP-70, 1-(3-{5-[(3-chlorobenzyl)sulfonyl]-1H-tetrazol-1-yl}phenyl)ethanone, SULFATE ION, ... (4 entities in total)
• Functional Keywords: tyrosine kinase, cysteine adduct, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 30100.76

Authors

Barros, T.,Kuriyan, J.,Visperas, P.R.,Winger, J.A. (deposition date: 2015-02-03, release date: 2015-06-17, Last modification date: 2023-09-27)

Primary citation

Visperas, P.R.,Winger, J.A.,Horton, T.M.,Shah, N.H.,Aum, D.J.,Tao, A.,Barros, T.,Yan, Q.,Wilson, C.G.,Arkin, M.R.,Weiss, A.,Kuriyan, J.
Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding.
Biochem. J., 465:149-161, 2015

PubMed 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.

PubMed: 25287889
DOI: 10.1042/BJ20140793

Experimental method

X-RAY DIFFRACTION (2 Å)