2. Academic Validation
  3. Structural insights into the activation of TMEM175 by small molecule

Structural insights into the activation of TMEM175 by small molecule

  • Neuron. 2025 Aug 22:S0896-6273(25)00556-2. doi: 10.1016/j.neuron.2025.07.029.
Xuewu Zhu 1,  Meixuan Ping 2,  Heng Liu 3,  Ting Yu 4,  Zhongwen Jiang 5,  Zhenhua Liu 6,  Chanjing Li 7,  Xinjiao Hou 3,  Qinyu Chu 8,  Shuyao Li 9,  Caiwen Mao 2,  Ting Luo 10,  Chunlan Kang 9,  Feng Wang 11,  Chuanyan Yang 12,  Meiqin Tang 9,  Zhidong Jiang 3,  Zhaobing Gao 13,  Hong Liu 14,  H Eric Xu 14,  Beisha Tang 15,  Xi Cheng 16,  Wanchao Yin 17,  Yu Zhou 18,  Ping Li 19
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Department of Neurology & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 7 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 8 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 330106, China.
  • 9 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 10 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China.
  • 11 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; School of Pharmacy, Zunyi Medical University, Zunyi 563000, China.
  • 12 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China.
  • 13 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 14 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 15 Department of Neurology & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Neurology & Multi-omics Research Center for Brain Disorders, The First Affiliated Hospital University of South China, Hengyang 421001, China. Electronic address: bstang7398@163.com.
  • 16 University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 330106, China; Department of Pharmaceutical and Artificial Intelligence Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xichengeva@sjtu.edu.cn.
  • 17 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: wcyin@simm.ac.cn.
  • 18 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 330106, China; School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China. Electronic address: zhouyu@simm.ac.cn.
  • 19 Zhongshan Institute for Drug Discovery, SIMM, Zhongshan 528400, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, China; School of Pharmacy, Zunyi Medical University, Zunyi 563000, China. Electronic address: lipingt@simm.ac.cn.
PMID: 40865534 DOI: 10.1016/j.neuron.2025.07.029
Abstract

The upregulation of transmembrane protein 175 (TMEM175) has the potential to improve Parkinson's disease (PD) by aiding in the removal of α-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 α-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 α-synuclein levels in PD.

Keywords

Parkinson’s disease; TMEM175; agonist; binding site; lysosome.

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