Summary for 8VIC
| Entry DOI | 10.2210/pdb8vic/pdb |
| EMDB information | 43257 |
| Descriptor | Endosomal/lysosomal potassium channel TMEM175, (2P,2'P)-2,2'-(1,3-phenylene)di(pyridin-4-amine) (2 entities in total) |
| Functional Keywords | ion channel, lysosome, potassium channel, transport protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 111596.75 |
| Authors | Oh, S.,Hite, R.K. (deposition date: 2024-01-03, release date: 2024-08-14, Last modification date: 2025-02-26) |
| Primary citation | Oh, S.,Lee, J.,Choi, H.J.,Kim, S.,Sapuru, V.,Kim, M.,Hite, R.K. Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175. J.Am.Chem.Soc., 146:23230-23239, 2024 Cited by PubMed Abstract: TMEM175 is a lysosomal potassium and proton channel that is associated with the development of Parkinson's disease. Advances in understanding the physiological roles of TMEM175 have been hampered by the absence of selective inhibitors, and studies involving genetic perturbations have yielded conflicting results. Here, we report the discovery and characterization of the first reported TMEM175-selective inhibitors, 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes. These inhibitors may serve as valuable tools to study the roles of TMEM175 in regulating lysosomal function and provide useful templates for future therapeutic development in Parkinson's disease. PubMed: 39116214DOI: 10.1021/jacs.4c05623 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.48 Å) |
Structure validation
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