Drug inhibition and substrate transport mechanisms of human VMAT2
Abstract Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson’s disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, ar...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55361-0 |
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| author | Feiwen Wei Huihui Liu Wei Zhang Jufang Wang Yanqing Zhang |
| author_facet | Feiwen Wei Huihui Liu Wei Zhang Jufang Wang Yanqing Zhang |
| author_sort | Feiwen Wei |
| collection | DOAJ |
| description | Abstract Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson’s disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders. |
| format | Article |
| id | doaj-art-f4cb7cf3eeab419dba74dec0869370ed |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f4cb7cf3eeab419dba74dec0869370ed2025-01-05T12:39:39ZengNature PortfolioNature Communications2041-17232025-01-0116111110.1038/s41467-024-55361-0Drug inhibition and substrate transport mechanisms of human VMAT2Feiwen Wei0Huihui Liu1Wei Zhang2Jufang Wang3Yanqing Zhang4Shanghai Fifth People’s Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityArieh Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong KongShanghai Fifth People’s Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityShanghai Fifth People’s Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityShanghai Fifth People’s Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityAbstract Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson’s disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders.https://doi.org/10.1038/s41467-024-55361-0 |
| spellingShingle | Feiwen Wei Huihui Liu Wei Zhang Jufang Wang Yanqing Zhang Drug inhibition and substrate transport mechanisms of human VMAT2 Nature Communications |
| title | Drug inhibition and substrate transport mechanisms of human VMAT2 |
| title_full | Drug inhibition and substrate transport mechanisms of human VMAT2 |
| title_fullStr | Drug inhibition and substrate transport mechanisms of human VMAT2 |
| title_full_unstemmed | Drug inhibition and substrate transport mechanisms of human VMAT2 |
| title_short | Drug inhibition and substrate transport mechanisms of human VMAT2 |
| title_sort | drug inhibition and substrate transport mechanisms of human vmat2 |
| url | https://doi.org/10.1038/s41467-024-55361-0 |
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