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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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