Structural insights into the activation of TMEM175 by small molecule
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.
Authors
- Meiqin Tang
- Chuanyan Yang (ORCID: https://orcid.org/0000-0002-4945-1166)
- Shuyao Li (ORCID: https://orcid.org/0000-0003-2156-4684)
- C Li
- Beisha Tang
- Chunyou Mao (ORCID: https://orcid.org/0000-0001-5349-8592)
- Xiaohua Hou (ORCID: https://orcid.org/0000-0002-3694-2126)
- Zhengxuan Jiang (ORCID: https://orcid.org/0000-0001-7620-8658)
- H. Eric Xu (ORCID: https://orcid.org/0000-0002-6829-8144)
- Ting Yu (ORCID: https://orcid.org/0000-0002-0113-2895)
- Feng Wang
- Zhaobing Gao (ORCID: https://orcid.org/0000-0001-8931-5508)
- Wanchao Yin (ORCID: https://orcid.org/0000-0002-6889-4907)
- Xuewu Zhu (ORCID: https://orcid.org/0000-0003-2939-3111)
- Heng Liu (ORCID: https://orcid.org/0000-0003-2654-4287)
- Hong Liu (ORCID: https://orcid.org/0000-0002-8044-4781)
- Zhenhua Liu (ORCID: https://orcid.org/0000-0003-1926-6020)
- Ping Li (ORCID: https://orcid.org/0000-0003-1871-176X)
- Zhidong Jiang
- Chunlan Kang
- Xi Cheng
- Qinyu Chu
- Meixuan Ping
- Yu Zhou (ORCID: https://orcid.org/0009-0009-6486-9120)
- Ting Luo
Institutions
- Nanjing University of Chinese Medicine (CN)
- Central South University (CN)
- Guiyang Medical University (CN)
- China Pharmaceutical University (CN)
- Zunyi Medical University (CN)
- Guangdong Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
- National Clinical Research (US)
- Zhongshan Hospital (CN)
- China Academy of Chinese Medical Sciences (CN)
- First Affiliated Hospital of University of South China (CN)
- Xiangya Hospital Central South University (CN)
- Southern Medical University (CN)
- University of South China (CN)
Publication Details
- Journal
- Neuron
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1016/j.neuron.2025.07.029
- Citations
- 3
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 2.42