Structural insights into the activation of TMEM175 by small molecule
Xuewu Zhu, Meixuan Ping, Heng Liu, Ting Yu, Zhongwen Jiang, Zhenhua Liu, C Li, Xinjiao Hou, Qinyu Chu, Shuyao Li, Caiwen Mao, Ting Luo, Chunlan Kang, Feng Wang, Chuanyan Yang, Meiqin Tang, Zhidong Jiang, Zhaobing Gao, Hong Liu, H. Eric Xu, Beisha Tang, Xi Cheng, Wanchao Yin, Yu Zhou, Ping Li
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.