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TitleDiscovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175.
Journal, issue, pagesJ Am Chem Soc, Vol. 146, Issue 33, Page 23230-23239, Year 2024
Publish dateAug 21, 2024
AuthorsSeCheol Oh / Jooyeon Lee / Ho Jeong Choi / Songwon Kim / Vinay Sapuru / Min Kim / Richard K Hite /
PubMed AbstractTMEM175 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 ...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.
External linksJ Am Chem Soc / PubMed:39116214 / PubMed Central
MethodsEM (single particle)
Resolution3.48 - 3.52 Å
Structure data

43257

8vic

EMDB-43257, PDB-8vic:
AP-6 bound human TMEM175
Method: EM (single particle) / Resolution: 3.48 Å

43259

8vie

EMDB-43259, PDB-8vie:
2-PPA bound human TMEM175
Method: EM (single particle) / Resolution: 3.52 Å

Chemicals

PDB-1aa3:
C-TERMINAL DOMAIN OF THE E. COLI RECA, NMR, MINIMIZED AVERAGE STRUCTURE

PDB-1ab0:
C1G/V32D/F57H MUTANT OF MURINE ADIPOCYTE LIPID BINDING PROTEIN AT PH 4.5

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Ion Channel / Lysosome / Potassium Channel / MEMBRANE PROTEIN

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