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Dysfunction of VMAT2 causes many neuropsychiatric disorders, such as depression and Parkinson's disease. Consequently, VMAT2 is a valid and important therapeutic target. Reserpine alleviates symptoms of hypertension via potent inhibition of VMAT2. Tetrabenazine selectively inhibits VMAT2 and has been used for the management of chorea, including Huntington's disease. Decades of extensive studies have defined the substrate specificity and transport kinetics of VMAT2. However, the structure and precise mechanisms of monoamine recognition and drug inhibition in VMAT2 remain unknown. Recently, we determined an ensemble of high\u2010resolution cryo\u2010EM structures of human VMAT2 in three distinct states bound to multiple substrates and inhibitors. These results lay a structural foundation for a comprehensive understanding of substrate recognition and transport, drug inhibition, and proton coupling in VMAT2 and shed light on future therapeutic development.<\/jats:p>","DOI":"10.1111\/febs.70003","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:20:06Z","timestamp":1738282806000},"page":"4789-4796","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structural insights into substrate transport and drug inhibition of the human vesicular monoamine transporter 2 (\n                    <scp>VMAT2<\/scp>\n                    )"],"prefix":"10.1111","volume":"292","author":[{"given":"Di","family":"Wu","sequence":"first","affiliation":[{"name":"Laboratory of Soft Matter Physics, Institute of Physics Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing 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