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J. Am. Chem. Soc., Aug 08 2024, | https://doi.org/10.1021/jacs.4c05623
Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175
SeCheol Oh 1, Jooyeon Lee 2, Ho Jeong Choi 2, Songwon Kim 1, Vinay Sapuru 1,3, Min Kim 2, Richard K Hite 1
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
2Department of Chemistry, Chungbuk National University, Cheongju 28644, Republic of Korea.
3Physiology, Biophysics, and Systems Biology (PBSB) Program, Weill Cornell Graduate School of Biomedical Sciences, 1300 York Avenue, New York, New York 10065, United States.
Corresponding Author : Richard K. Hite
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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-12)
- 국외 연구진
- 생명과학 > 생화학
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