分类： 生物学 >> 生物物理学 提交时间： 2016-05-15
Dong, Jing
Zhang, Yong
Zhang, Yu
Deng, Xuming
Dong, Jing
Chen, Yutao
Wang, Quan
Li, Xuemei
Niu, Xiaodi
Yang, Cheng
摘要： Shiga-like toxins (Stxs), produced by pathogenic Escherichia coli, are a major virulence factor involved in severe diseases in human and animals. These toxins are ribosome-inactivating proteins, and treatment for diseases caused by them is not available. Therefore, there is an urgent need for agents capable of effectively targeting this lethal toxin. In this study, we identified baicalin, a flavonoid compound used in Chinese traditional medicine, as a compound against Shiga-like toxin 2 (Stx2). We found that baicalin significantly improves renal function and reduces Stx2-induced lethality in mice. Further experiments revealed that baicalin induces the formation of oligomers by the toxin by direct binding. We also identified the residues important for such interactions and analyzed their roles in binding baicalin by biophysical and biochemical analyses. Our results establish baicalin as a candidate compound for the development of therapeutics against diseases caused by Stxs.
分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-12
Dong, Jing
Zhang, Yong
Zhang, Yu
Li, Rui
Deng, Xuming
Dong, Jing
Chen, Yutao
Wang, Quan
Li, Xuemei
Niu, Xiaodi
Yang, Cheng
摘要： Toxic ribosome-inactivating proteins abolish cell viability by inhibiting protein synthesis. Ricin, a member of these lethal proteins, is a potential bioterrorism agent. Despite the grave challenge posed by these toxins to public health, post-exposure treatment for intoxication caused by these agents currently is unavailable. In this study, we report the identification of baicalin extracted from Chinese herbal medicine as a compound capable of inhibiting the activity of ricin. More importantly, post-exposure treatment with baicalin significantly increased the survival of mice poisoned by ricin. We determined the mechanism of action of baicalin by solving the crystal structure of its complex with the A chain of ricin (RTA) at 2.2 angstrom resolution, which revealed that baicalin interacts with two RTA molecules at a novel binding site by hydrogen bond networks and electrostatic force interactions, suggesting its role as molecular glue of the RTA. Further biochemical and biophysical analyses validated the amino acids directly involved in binding the inhibitor, which is consistent with the hypothesis that baicalin exerts its inhibitory effects by inducing RTA to form oligomers in solution, a mechanism that is distinctly different from previously reported inhibitors. This work offers promising leads for the development of therapeutics against ricin and probably other ribosome-inactivating proteins.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Cao, Shujuan
Yu, Liang
Ruan, Jishou
Cao, Shujuan
Yu, Liang
Ruan, Jishou
Mao, Jingyuan
Wang, Quan
Wang, Quan
Ruan, Jishou
摘要： This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (A beta) and acetylcholine (ACh) which stimulate the Alzheimer's Disease (AD). Then we generate the AD network by incorporating MMNs of A beta and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as A beta deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before A beta deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further.
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