分类： 药物科学 >> 生物化学 提交时间： 2024-06-14
Huixu Feng
Guobin Liu
Luhan Li
Xuelian Ren
Yue Jiang
Wanting Hou
Ruilong Liu
Kun Liu
Hong Liu
He Huang
摘要： Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine’s regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine’s impact on hyperlipidemia. Moreover, matrine’s potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, Thermal Proteome Profiling (TPP) analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine’s capacity to upregulate LDLR expression and highlights its potential in treating hyperlipidemia. These findings offer insights into matrine’s mechanism of action and open new avenues for drug research and lipid metabolism regulation.
分类： 药物科学 >> 结构生物学 提交时间： 2024-04-27
Heng Zhang
Yuling Yin
Tianwei Zhang
Canrong Wu
Wen Hu
Xinheng He
Benxun Pan
Sanshan Jin
Qingning Yuan
H. Eric Xu
Yi Jiang
摘要： The norepinephrine transporter (NET) plays a pivotal role in regulating neurotransmitter balance and is critical for normal physiology and neurobiology. Dysfunction of NET has been implicated in numerous neuropsychiatric diseases including depression, anxiety, attention deficit hyperactivity disorder, and Parkinson’s disease. Here we report cryo-EM structures of NET in apo and substrate-bound forms, as well as complexes with six antidepressants. The structures reveal an unexpected NET dimer interface predominantly mediated by cholesterol and lipid molecules. The substrate norepinephrine is found to bind deep within the central binding pocket, with its amine group interacting with a conserved aspartate. The structures also provide insight into antidepressant recognition, including how subtle differences in binding poses confer selectivity over other monoamine transporters. Together these breakthrough findings significantly advance our understanding of NET regulation and inhibition, providing templates for designing improved antidepressants to treat neuropsychiatric disorders.
分类： 药物科学 >> 结构生物学 提交时间： 2024-02-24
Heng Liu
Shimeng Guo
Antao Dai
Peiyu Xu
Xin Li
Sijie Huang
Xinheng He
Kai Wu
Xinyue Zhang
Dehua Yang
Xin Xie
H. Eric Xu
摘要： The orphan receptor GPR30, previously classified as a G protein-coupled estrogen receptor (GPER), has been a subject of debate regarding its ligand specificity. Through an integrative approach combining structure elucidation, biochemical binding, and cell signaling assays, we demonstrate that estrogen does not directly bind to or activate GPR30. Cryo-EM structures of GPR30 reveal an unexpected hydrophilic ligand-binding pocket, with striking differences from classical hydrophobic steroid-binding sites, inconsistent with estrogen binding. We further confirmed hydrophilic agonists like Lys05 as true activators of GPR30, providing structural insights into their binding mechanism and receptor activation. Our findings necessitate a paradigm shift in defining GPR30’s role in estrogen signaling, indicating that its activation occurs through mechanisms independent of estrogen binding. This study opens new avenues for developing targeted GPR30 ligands and reinterpreting its role in estrogen-mediated processes.
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