气候变化领域集成服务门户(CCPortal): Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

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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
	Stadler, Karina A.; Ortiz-Joya, Lesly J.; Singh Sahrawat, Amit; Buhlheller, Christoph; Gruber, Karl; Pavkov-Keller, Tea; O'Hagan, Treasa B.; Guarne, Alba; Pulido, Sergio; Marin-Villa, Marcel; Zangger, Klaus; Gubensaek, Nina
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/296894
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	Stadler, Karina A.,Ortiz-Joya, Lesly J.,Singh Sahrawat, Amit,et al. Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease[J],2024,14(1).
APA	Stadler, Karina A..,Ortiz-Joya, Lesly J..,Singh Sahrawat, Amit.,Buhlheller, Christoph.,Gruber, Karl.,...&Gubensaek, Nina.(2024).Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease.SCIENTIFIC REPORTS,14(1).
MLA	Stadler, Karina A.,et al."Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease".SCIENTIFIC REPORTS 14.1(2024).