Structural mechanisms for VMAT2 inhibition by tetrabenazine
The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Furthermore, drugs such as...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/91973 |
| _version_ | 1797248537460736000 |
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| author | Michael P Dalton Mary Hongying Cheng Ivet Bahar Jonathan A Coleman |
| author_facet | Michael P Dalton Mary Hongying Cheng Ivet Bahar Jonathan A Coleman |
| author_sort | Michael P Dalton |
| collection | DOAJ |
| description | The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2’s importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington’s chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics. |
| first_indexed | 2024-04-24T20:16:10Z |
| format | Article |
| id | doaj.art-393c81c8a92d464781df40f53e029e46 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T20:16:10Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-393c81c8a92d464781df40f53e029e462024-03-22T16:39:01ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011210.7554/eLife.91973Structural mechanisms for VMAT2 inhibition by tetrabenazineMichael P Dalton0https://orcid.org/0000-0001-5296-5099Mary Hongying Cheng1https://orcid.org/0000-0001-5833-8221Ivet Bahar2Jonathan A Coleman3https://orcid.org/0000-0003-0001-6195Department of Structural Biology, University of Pittsburgh, Pittsburgh, United StatesLaufer Center for Physical and Quantitative Biology, and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United StatesLaufer Center for Physical and Quantitative Biology, and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, United StatesDepartment of Structural Biology, University of Pittsburgh, Pittsburgh, United StatesThe vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2’s importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington’s chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.https://elifesciences.org/articles/91973membrane transportneurotransmitterssmall-molecule inhibitors |
| spellingShingle | Michael P Dalton Mary Hongying Cheng Ivet Bahar Jonathan A Coleman Structural mechanisms for VMAT2 inhibition by tetrabenazine eLife membrane transport neurotransmitters small-molecule inhibitors |
| title | Structural mechanisms for VMAT2 inhibition by tetrabenazine |
| title_full | Structural mechanisms for VMAT2 inhibition by tetrabenazine |
| title_fullStr | Structural mechanisms for VMAT2 inhibition by tetrabenazine |
| title_full_unstemmed | Structural mechanisms for VMAT2 inhibition by tetrabenazine |
| title_short | Structural mechanisms for VMAT2 inhibition by tetrabenazine |
| title_sort | structural mechanisms for vmat2 inhibition by tetrabenazine |
| topic | membrane transport neurotransmitters small-molecule inhibitors |
| url | https://elifesciences.org/articles/91973 |
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