skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen

Journal Article · · SLAS DISCOVERY: Advancing Life Sciences R&D
 [1];  [2];  [1];  [1];  [1];  [2];  [3];  [4]
  1. Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences and Howard Hughes Medical Inst., Dept. of Molecular and Cell Biology and Department of Chemistry
  2. Univ. of California, San Francisco, CA (United States). Small Molecule Discovery Center, Dept. of Pharmaceutical Chemistry
  3. Univ. of California, San Francisco, CA (United States). Rosalind Russell and Ephrain P. Engleman Rheumatology Research Center for Arthritis and Howard Hughes Medical Inst., Dept. of Medicine
  4. Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences and Howard Hughes Medical Inst., Dept. of Molecular and Cell Biology and Department of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
+ Show Author Affiliations

ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular ζ-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor. Finally, the screen is based on a fluorescence polarization assay for peptide binding to ZAP-70.

Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1379661
Journal Information:
SLAS DISCOVERY: Advancing Life Sciences R&D, Vol. 22, Issue 3; ISSN 2472-5552
Publisher:
SAGECopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 11 works
Citation information provided by
Web of Science

References (6)

Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding journal December 2014
ZAP-70: An Essential Kinase in T-cell Signaling journal May 2010
Structural Basis for the Inhibition of Tyrosine Kinase Activity of ZAP-70 journal May 2007
Structural Basis for Activation of ZAP-70 by Phosphorylation of the SH2-Kinase Linker journal March 2013
Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor journal September 1995
Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases journal February 1994

Similar Records

A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70
Journal Article · Mon Jan 18 00:00:00 EST 2016 · Journal of Experimental Medicine · OSTI ID:1379661
+10 more
Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4
Journal Article · Fri Apr 10 00:00:00 EDT 2009 · Biochemical and Biophysical Research Communications · OSTI ID:1379661
+1 more
Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4)
Journal Article · Thu Jan 24 00:00:00 EST 2019 · Journal of Biological Chemistry · OSTI ID:1379661
+5 more

Related Subjects

60 APPLIED LIFE SCIENCES
T cell
ZAP-70
fluorescence polarization (FP)
time-resolved fluorescence resonance energy transfer (TR-FRET)
covalent inhibitor
kinase