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Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175
Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson’s disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only kno...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636928/ https://www.ncbi.nlm.nih.gov/pubmed/36279431 http://dx.doi.org/10.1073/pnas.2208882119 |
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author | Oh, SeCheol Stix, Robyn Zhou, Wenchang Faraldo-Gómez, José D. Hite, Richard K. |
author_facet | Oh, SeCheol Stix, Robyn Zhou, Wenchang Faraldo-Gómez, José D. Hite, Richard K. |
author_sort | Oh, SeCheol |
collection | PubMed |
description | Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson’s disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only known small-molecule inhibitor of TMEM175 and a broad K(+) channel inhibitor, as well as a drug approved by the Food and Drug Administration against multiple sclerosis. The structure shows that 4-AP, whose mode of action had not been previously visualized, binds near the center of the ion conduction pathway, in the open state of the channel. Molecular dynamics simulations reveal that this binding site is near the middle of the transmembrane potential gradient, providing a rationale for the voltage-dependent dissociation of 4-AP from TMEM175. Interestingly, bound 4-AP rapidly switches between three predominant binding poses, stabilized by alternate interaction patterns dictated by the twofold symmetry of the channel. Despite this highly dynamic binding mode, bound 4-AP prevents not only ion permeation but also water flow. Together, these studies provide a framework for the rational design of novel small-molecule inhibitors of TMEM175 that might reveal the role of this channel in human lysosomal physiology both in health and disease. |
format | Online Article Text |
id | pubmed-9636928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-96369282023-04-24 Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 Oh, SeCheol Stix, Robyn Zhou, Wenchang Faraldo-Gómez, José D. Hite, Richard K. Proc Natl Acad Sci U S A Biological Sciences Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson’s disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only known small-molecule inhibitor of TMEM175 and a broad K(+) channel inhibitor, as well as a drug approved by the Food and Drug Administration against multiple sclerosis. The structure shows that 4-AP, whose mode of action had not been previously visualized, binds near the center of the ion conduction pathway, in the open state of the channel. Molecular dynamics simulations reveal that this binding site is near the middle of the transmembrane potential gradient, providing a rationale for the voltage-dependent dissociation of 4-AP from TMEM175. Interestingly, bound 4-AP rapidly switches between three predominant binding poses, stabilized by alternate interaction patterns dictated by the twofold symmetry of the channel. Despite this highly dynamic binding mode, bound 4-AP prevents not only ion permeation but also water flow. Together, these studies provide a framework for the rational design of novel small-molecule inhibitors of TMEM175 that might reveal the role of this channel in human lysosomal physiology both in health and disease. National Academy of Sciences 2022-10-24 2022-11-01 /pmc/articles/PMC9636928/ /pubmed/36279431 http://dx.doi.org/10.1073/pnas.2208882119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Oh, SeCheol Stix, Robyn Zhou, Wenchang Faraldo-Gómez, José D. Hite, Richard K. Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title | Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title_full | Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title_fullStr | Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title_full_unstemmed | Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title_short | Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175 |
title_sort | mechanism of 4-aminopyridine inhibition of the lysosomal channel tmem175 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636928/ https://www.ncbi.nlm.nih.gov/pubmed/36279431 http://dx.doi.org/10.1073/pnas.2208882119 |
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