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Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson\u2019s 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\u2019s importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 \u00c5 resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington\u2019s 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.<\/jats:p>","DOI":"10.7554\/elife.91973","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T12:07:46Z","timestamp":1697544466000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91973","source":"Crossref","is-referenced-by-count":7,"title":["Structural mechanisms for VMAT2 inhibition by tetrabenazine"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5296-5099","authenticated-orcid":true,"given":"Michael P","family":"Dalton","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Structural Biology, University of Pittsburgh","place":["Pittsburgh, United 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