9vsr
The DCY1040 and TUG-891-bound structure of TMEM175
Structural highlights
DiseaseTM175_HUMAN Disease susceptibility may be associated with variations affecting the gene represented in this entry. TMEM175 defects result in unstable lysosomal pH, leading to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome and decreased mitochondrial respiration (PubMed:28193887).[1] FunctionTM175_HUMAN Organelle-specific potassium channel specifically responsible for potassium conductance in endosomes and lysosomes. Forms a potassium-permeable leak-like channel, which regulates lumenal pH stability and is required for autophagosome-lysosome fusion. Constitutes the major lysosomal potassium channel.[2] [3] Publication Abstract from PubMedThe 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. Structural insights into the activation of TMEM175 by small molecule.,Zhu X, Ping M, Liu H, Yu T, Jiang Z, Liu Z, Li C, Hou X, Chu Q, Li S, Mao C, Luo T, Kang C, Wang F, Yang C, Tang M, Jiang Z, Gao Z, Liu H, Xu HE, Tang B, Cheng X, Yin W, Zhou Y, Li P Neuron. 2025 Aug 22:S0896-6273(25)00556-2. doi: 10.1016/j.neuron.2025.07.029. PMID:40865534[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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