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DOI | 10.1016/j.scib.2021.01.023 |
Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects | |
Feng L.; Lu S.; Zheng Z.; Chen Y.; Zhao Y.; Song K.; Xue H.; Jin L.; Li Y.; Huang C.; Li Y.-M.; Zhang J. | |
发表日期 | 2021 |
ISSN | 20959273 |
起始页码 | 1559 |
结束页码 | 1570 |
卷号 | 66期号:15 |
英文摘要 | Thiazolidinediones (TZDs), such as rosiglitazone (RSG), which activates peroxisome proliferator activated receptor-γ (PPARγ), are a potent class of oral antidiabetic agents with good durability. However, the clinical use of TZDs is challenging because of their side effects, including weight gain and hepatotoxicity. Here, we found that bavachinin (BVC), a lead natural product, additively activates PPARγ with low-dose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy. Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARγ, thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG. Based on this hotspot, we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC. Together, our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists, and the combination therapy of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus. © 2021 Science China Press |
关键词 | Additive activationAllosteric hotspotCobindingCombination therapyPPARγSide effects |
英文关键词 | Additives; Cytology; Drug interactions; Mammals; Additive activation; Allosteric hotspot; Cobinding; Combination therapy; Hot spot; Peroxisome proliferator activated receptor-γ; Peroxisome proliferator-activated receptor; Rosiglitazone; Side effect; Thiazolidinediones; Chemical activation |
语种 | 英语 |
来源期刊 | Science Bulletin |
文献类型 | 期刊论文 |
条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/207395 |
作者单位 | Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, 201210, China; State Key Laboratory of Cellular Stress Biology, Innovation Centre for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China |
推荐引用方式 GB/T 7714 | Feng L.,Lu S.,Zheng Z.,et al. Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects[J],2021,66(15). |
APA | Feng L..,Lu S..,Zheng Z..,Chen Y..,Zhao Y..,...&Zhang J..(2021).Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects.Science Bulletin,66(15). |
MLA | Feng L.,et al."Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects".Science Bulletin 66.15(2021). |
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