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DOI10.1016/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
ISSN20959273
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
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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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