9vsr

From Proteopedia

The DCY1040 and TUG-891-bound structure of TMEM175

Structural highlights

9vsr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.92Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TM175_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]

Function

TM175_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 PubMed

The 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

↑ Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2389-2394. doi:, 10.1073/pnas.1616332114. Epub 2017 Feb 13. PMID:28193887 doi:http://dx.doi.org/10.1073/pnas.1616332114
↑ Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Function. Cell. 2015 Aug 27;162(5):1101-12. doi: 10.1016/j.cell.2015.08.002. PMID:26317472 doi:http://dx.doi.org/10.1016/j.cell.2015.08.002
↑ Lee C, Guo J, Zeng W, Kim S, She J, Cang C, Ren D, Jiang Y. The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature. 2017 Jul 27;547(7664):472-475. doi: 10.1038/nature23269. Epub 2017 Jul, 19. PMID:28723891 doi:http://dx.doi.org/10.1038/nature23269
↑ 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. Structural insights into the activation of TMEM175 by small molecule. Neuron. 2025 Aug 22:S0896-6273(25)00556-2. PMID:40865534 doi:10.1016/j.neuron.2025.07.029