biostudies-literatureWang YMinistry of Science and Technology of the People’s Republic of ChinaNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationMinistry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)National Natural Science Foundation of China (National Science Foundation of China)47-57https://www.ebi.ac.uk/biostudies/studies/S-EPMC10770148biostudies-literatureUnknown34(1)Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occludedCell researchTransport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.PMC107701482020YFA0509600822250252022M720805323712563207119732171194Liu YLi YQu QZhu ZLong YLi DWang SChao YWang YYang CZhang PZhou ZfalseTransport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded2024-01-01T00:00:00Z2024 Jan2026-07-15T14:08:52.903Z2025-07-27T03:11:00.306ZS-EPMC107701483816384610.1038/s41422-023-00906-z