Structure prediction of eukaryotic elongation factor-2 kinase and identification of the binding mechanisms of its inhibitors: homology modeling, molecular docking, and molecular dynamics simulation

Article

作者: AY, Mehmet ; Tatar, Gizem ; Ozpolat, Bulent ; Taskin Tok, Tugba

Protein kinases emerged as one of the most successful families of drug targets due to their increased activity and involvement in mediating critical signal transduction pathways in cancer cells. Recent evidence suggests that eukaryotic elongation factor 2 kinase (eEF-2K) is a potential therapeutic target for treating some highly aggressive solid cancers, including lung, pancreatic and triple-negative breast cancers. Thus, several compounds have been developed for the inhibition of the enzyme activity, but they are not sufficiently specific and potent. Besides, the crystal structure of this kinase remains unknown. Hence, the functional organization and regulation of eEF-2K remain poorly characterized. For this purpose, we constructed a homology model of eEF-2K and then used docking methodology to better understanding the binding mechanism of eEF-2K with 58 compounds that have been proposed as existing inhibitors. The results of this analysis were compared with the experimental results and the compounds effective against eEF-2K were determined against eEF-2K as a result of both studies. And finally, molecular dynamics (MD) simulations were performed for the stability of eEF-2K with these compounds. According to these study defined that the binding mechanism of eEF-2K with inhibitors at the molecular level and elucidated the residues of eEF-2K that play an important role in enzyme selectivity and ligand affinity. This information may lead to new selective and potential drug molecules to be for inhibition of eEF-2K.Communicated by Ramaswamy H. Sarma.

2022-10-01·Journal of Biochemical and Molecular Toxicology

eEF‐2K knockdown synergizes with STS treatment to inhibit cell proliferation, migration, and invasion via the TG2/ERK pathway in A549 cells

Article

作者: Wang, Bu ; Huang, Pan‐Deng ; Zhang, Chang‐Hong ; Zhang, Zhi‐Hua ; Zhao, Jian‐Qing ; Xiang, Bao‐Li ; Gu, Xin

AbstractEmerging research has suggested the anticancer potential of tanshinone IIA, the bioactive ingredient isolated from the traditional Chinese herb Salvia miltiorrhiza. However, the molecular mechanism of sodium tanshinone IIA sulfonate (STS) antilung cancer effect is not very clear. In this study, our purpose is to investigate the roles of STS and elongation factor‐2 kinase (eEF‐2K) in regulating the proliferation, migration, and invasion of A549 cells and explore the implicated pathways. We found that STS suppressed A549 cell survival and proliferation in a time‐ and xdose‐dependent manner. Knockdown of eEF‐2K and treatment with STS synergistically exerted antiproliferative, ‐migratory, and ‐invasive effects on A549 cells. These effects were caused by attenuation of the extracellular signal‐regulated kinase (ERK) pathway via inhibition of tissue transglutaminase (TG2). In summary, the inhibition of eEF‐2K synergizes with STS treatment, exerting anticancer effects on lung adenocarcinoma cells through the TG2/ERK signaling pathway, which provides a potential therapeutic target for treating lung adenocarcinoma.

2022-02-04·Science Advances1区 · 综合性期刊

Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8 ⁺ T cells

1区 · 综合性期刊

ArticleOA

作者: Alaniz, Robert C. ; Xiong, Xiaofang ; Yang, Jin-Ming ; Peng, Hao-Yun ; Das, Jugal Kishore ; Song, Jianxun ; Ren, Yijie ; Kumar, Anil ; Ren, Xingcong ; Liu, Xiaoqi ; Wang, Liqing ; Ryazonov, Alexey G. ; de Figueiredo, Paul

eEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8 + T cells. CD8 + T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8 + T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8 + T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8 + T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8 + T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8 + T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.

100 项与 eEF2K (Johns Hopkins University) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	药物发现	美国	Johns Hopkins Technology Ventures	-
阿尔茨海默症	药物发现	美国	The Johns Hopkins University	-
唐氏综合征	药物发现	美国	The Johns Hopkins University	-
唐氏综合征	药物发现	美国	Johns Hopkins Technology Ventures	-
脆性X综合征	药物发现	美国	Johns Hopkins Technology Ventures	-
脆性X综合征	药物发现	美国	The Johns Hopkins University	-
肿瘤	药物发现	美国	University of Medicine & Dentistry of New Jersey	-