Back to Search
Start Over
Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70
- Source :
- Molecules, Molecules, Vol 24, Iss 2, p 350 (2019), Volume 24, Issue 2
- Publication Year :
- 2018
-
Abstract
- A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, &alpha<br />epoxyarglabin, cytisinyl epoxyarglabin, 1 &beta<br />10 &alpha<br />epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04&ndash<br />5.3 &Aring<br />for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an &alpha<br />methylene- &gamma<br />lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.
- Subjects :
- ZAP-70
Pharmaceutical Science
Cell Communication
Sesquiterpene lactone
01 natural sciences
Jurkat cells
Analytical Chemistry
Jurkat Cells
Lactones
Drug Discovery
Phosphorylation
extracellular signal-regulated kinase
chemistry.chemical_classification
0303 health sciences
ZAP-70 Protein-Tyrosine Kinase
integumentary system
Molecular Structure
Biological activity
hemic and immune systems
Glutathione
3. Good health
Molecular Docking Simulation
Chemistry (miscellaneous)
Molecular Medicine
Mitogen-Activated Protein Kinases
Tyrosine kinase
Sesquiterpenes
Protein Binding
Signal Transduction
Stereochemistry
Receptors, Antigen, T-Cell
T-Cell Receptor Activation
Article
lcsh:QD241-441
03 medical and health sciences
Structure-Activity Relationship
lcsh:Organic chemistry
sesquiterpene lactones
Calcium flux
Humans
Physical and Theoretical Chemistry
Protein Kinase Inhibitors
030304 developmental biology
calcium flux
010405 organic chemistry
molecular modeling
Organic Chemistry
T-cell receptor
0104 chemical sciences
chemistry
T cell receptor
Subjects
Details
- ISSN :
- 14203049
- Volume :
- 24
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Molecules (Basel, Switzerland)
- Accession number :
- edsair.doi.dedup.....45385536be9d2e270da27833b6486b95