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; Molecules; Vol. 24, iss. 2
| Parent link: | Molecules Vol. 24, iss. 2.— 2019.— [350, 18 p.] |
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| Tác giả của công ty: | |
| Tác giả khác: | , , , , , , , |
| Tóm tắt: | Title screen 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, ? -epoxyarglabin, cytisinyl epoxyarglabin, 1 ? ,10 ? -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 3.04–5.3 A 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 ? -methylene- ? -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation. |
| Ngôn ngữ: | Tiếng Anh |
| Được phát hành: |
2019
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| Những chủ đề: | |
| Truy cập trực tuyến: | https://doi.org/10.3390/molecules24020350 |
| Định dạng: | Điện tử Chương của sách |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=664242 |
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| 200 | 1 | |a 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 |f A. I. Khlebnikov, I. A. Schepetkin (Shchepyotkin), A. S. Kishkentaeva [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 62 tit.] | ||
| 330 | |a 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, ? -epoxyarglabin, cytisinyl epoxyarglabin, 1 ? ,10 ? -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 3.04–5.3 A 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 ? -methylene- ? -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation. | ||
| 461 | |t Molecules | ||
| 463 | |t Vol. 24, iss. 2 |v [350, 18 p.] |d 2019 | ||
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| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a sesquiterpene lactones | |
| 610 | 1 | |a ZAP-70 | |
| 610 | 1 | |a T cell receptor | |
| 610 | 1 | |a extracellular signal-regulated kinase | |
| 610 | 1 | |a calcium flux | |
| 610 | 1 | |a molecular modeling | |
| 610 | 1 | |a glutathione | |
| 610 | 1 | |a сесквитерпеновые лактоны | |
| 610 | 1 | |a рецепторы | |
| 610 | 1 | |a молекулярное моделирование | |
| 701 | 1 | |a Khlebnikov |b A. I. |c Chemist |c Professor of Tomsk Polytechnic University |f 1963- |g Andrey Ivanovich |3 (RuTPU)RU\TPU\pers\33927 |9 17500 | |
| 701 | 1 | |a Schepetkin (Shchepyotkin) |b I. A. |c doctor-biophysicist |c leading researcher of Tomsk Polytechnic University, candidate of medical science |f 1962- |g Igor Aleksandrovich |3 (RuTPU)RU\TPU\pers\37358 | |
| 701 | 1 | |a Kishkentaeva |b A. S. |g Anarkul Serikovna | |
| 701 | 1 | |a Shaimerdenova |b Zh. R. |g Zhanar Rakhimovna | |
| 701 | 1 | |a Atazhanova |b G. A. |g Gayane Abdulkakhimovna | |
| 701 | 1 | |a Adekenov |b S. M. |g Sergazy Mynzhasarovich | |
| 701 | 1 | |a Kirpotina |b L. N. |g Liliya Nikolaevna | |
| 701 | 1 | |a Quinn |b M. T. |g Mark | |
| 712 | 0 | 2 | |a Национальный исследовательский Томский политехнический университет |b Инженерная школа новых производственных технологий |b Научно-образовательный центр Н. М. Кижнера |3 (RuTPU)RU\TPU\col\23556 |
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