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  5. 原创新药研究全国重点实验室
Structural insights into the activation of TMEM175 by small molecule

文献类型：期刊论文

作者Zhu, Xuewu; Ping, Meixuan; Liu, Heng; Yu, Ting1,2,3,4; Jiang, Zhongwen2,4; Liu, Zhenhua2,4,5,6; Li, Chanjing2,4,7; Hou, Xinjiao2,3,4; Chu, Qinyu1,3,8; Li, Shuyao2,7
刊名NEURON
出版日期2025-11-05
卷号113期号:21页码:25
ISSN号0896-6273
DOI10.1016/j.neuron.2025.07.029
英文摘要The upregulation of transmembrane protein 175 (TMEM175) has the potential to improve Parkinson's disease (PD) by aiding in the removal of alpha-synuclein aggregates. Understanding the structural basis of TMEM175 agonisms is crucial for uncovering its therapeutic potential for PD. Here, we have identified the first cryo-electron microscopy (cryo-EM) structure of human TMEM175 complexes with three agonists: DCY1020, DCY1040, and TUG-891. An open state of TMEM175 is unequivocally captured, laying the groundwork for designing more effective agonists. Further investigations using surface plasmon resonance, systematic mutagenesis, whole-endolysosome patch-clamp techniques, and molecular dynamics simulations consistently revealed that DCY1020/1040 binds at the interface between two subunits, inducing an open conformation further augmented by the synergistic agonist TUG-891. Notably, these agonists facilitate the removal of pathological alpha-synuclein and restore functions of PD-related TMEM175 variants in neurons. Our findings provide proof of concept that drug discovery targeting TMEM175 can develop agonists capable of effectively reducing pathological alpha-synuclein levels in PD.
WOS关键词GENOME-WIDE ASSOCIATION ; PARKINSONS-DISEASE ; CHANNEL ; MODEL ; METAANALYSIS ; INHIBITION ; ALGORITHMS ; PROTEINS ; DYNAMICS ; GENES
资助项目National Key Research and Development Program of China[2021YFA1301900] ; National Natural Science Foundation of China[82273913] ; National Natural Science Foundation of China[32100621] ; National Natural Science Foundation of China[82173656] ; National Natural Science Foundation of China[82373709] ; National Natural Science Foundation of China[32171189] ; National Natural Science Foundation of China[U20A20355] ; National Science Fund for Excellent Young Scholars[82122067] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB0830000] ; Guangdong Basic and Applied Basic Research Foundation[2025B1515020003] ; Guangdong Basic and Applied Basic Research Foundation[2022A1515010851] ; Fund of Shanghai Oriental Elite Talent Program[QNKJ2024005] ; Shanghai Municipal Science and Technology Major Project ; Science and Technology Major Project of Hunan Provincial Science and Technology Department[2021SK1010] ; Fund of Youth Innovation Promotion Association[2022077] ; Fund of Youth Innovation Promotion Association[2021278] ; Zhongshan Municipal Bureau of Science and Technology[220418134367984] ; Zhongshan Municipal Bureau of Science and Technology[CXTD2022013] ; Zhongshan Municipal Bureau of Science and Technology[CXTD2023010] ; High-level new RD institute[2019B090904008] ; High-Level Innovative Research Institute from Department of Science and Technology of Guangdong Province[2021B0909050003] ; Sanofi Scholarship Program
WOS研究方向Neurosciences & Neurology
语种英语
WOS记录号WOS:001616119900006
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/321980]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Tang, Beisha; Cheng, Xi; Yin, Wanchao; Zhou, Yu; Li, Ping
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.SIMM, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China
5.Cent South Univ, Xiangya Hosp, Dept Neurol, Changsha, Peoples R China
6.Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China
7.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
8.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 330106, Peoples R China
9.Guizhou Med Univ, Sch Pharmaceut Sci, Guiyang 550025, Peoples R China
10.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Xuewu,Ping, Meixuan,Liu, Heng,et al. Structural insights into the activation of TMEM175 by small molecule[J]. NEURON,2025,113(21):25.
APA Zhu, Xuewu.,Ping, Meixuan.,Liu, Heng.,Yu, Ting.,Jiang, Zhongwen.,...&Li, Ping.(2025).Structural insights into the activation of TMEM175 by small molecule.NEURON,113(21),25.
MLA Zhu, Xuewu,et al."Structural insights into the activation of TMEM175 by small molecule".NEURON 113.21(2025):25.

入库方式： OAI收割

来源：上海药物研究所

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