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| DOI | 10.1038/s41598-024-59654-8 |
| Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease | |
| 发表日期 | 2024 |
| ISSN | 2045-2322 |
| 起始页码 | 14 |
| 结束页码 | 1 |
| 卷号 | 14期号:1 |
| 英文摘要 | According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions. |
| 英文关键词 | American trypanosomiasis; Parasitic disease; NMR; Akt/PKB; PH domain |
| 语种 | 英语 |
| WOS研究方向 | Science & Technology - Other Topics |
| WOS类目 | Multidisciplinary Sciences |
| WOS记录号 | WOS:001214873000007 |
| 来源期刊 | SCIENTIFIC REPORTS
 |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/296893 |
| 作者单位 | University of Graz; Universidad de Antioquia; University of Graz; University of Graz; McGill University |
| 推荐引用方式 GB/T 7714 | . Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease[J],2024,14(1). |
| APA | (2024).Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease.SCIENTIFIC REPORTS,14(1). |
| MLA | "Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease".SCIENTIFIC REPORTS 14.1(2024). |
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