title: Baicalin inhibits the lethality of ricin in mice by inducing protein oligomerization.
abstract: 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 Å 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.
authors.affiliation: From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, the Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: the Department of Food Quality and Safety, Jilin University, Changchun 130062, and.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Niu
authors.affiliation: From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: the College of Pharmacy, NanKai University, Tianjin 300071, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, lixm@sun5.ibp.ac.cn.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, dengxm@jlu.edu.cn.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D008516:Medicine, Chinese Traditional; D051379:Mice; D008807:Mice, Inbred BALB C; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012276:Ricin / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; C038044:baicalin; D012276:Ricin
keywords: baicalin; biophysics; crystal structure; enzyme inhibitor; oligomerization; protein structure; ricin; small molecule
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