Inhibition of the T-cell Kinase ZAP-70

摘要: Author(s): Visperas, Patrick Ramos | Advisor(s): Kuriyan, John Abstract: The adaptive immune system responds to foreign antigens produce a highly specific response. T-cells, type of white blood cell the system, can either directly kill infected cells or aid in sending signals that regulate T-cell receptor is expressed on surface T-cells and recognizes presented by antigen presenting cells. Unlike transmembrane tyrosine kinases, does not contain its own kinase activity. Rather, recruits number non-receptor kinases upon extracellular binding trigger intracellular signaling cascades. Zeta-chain associated protein 70-kDa (ZAP-70) one such recruited regions known as Immuno-receptor Tyrosine-based Activation Motifs (ITAMs). Clinical observations, well chemical genetic studies, suggest ZAP-70 possible target for inhibition.Small molecule inhibitors may prove be therapeutically useful treatment autoimmune disease organ transplant rejection. Because no molecules exist today, we hope exploit structural insights gleaned from recently solved autoinhibited structure discover an allosteric inhibitor. In this dissertation, I describe method inhibiting interaction between receptor. performed high throughput screen ZAP-70:ITAM identified collection hit compounds. Inhibition these compounds was verified orthogonal assay dose-dependent. found targeted tandem-SH2 domains were thiol-reactive. go show covalent cysteine modification underlies inhibition individual are different residues.