EMD-41068

Single-particle
3.72 Å
EMD-41068 Deposition: 15/06/2023
Map released: 01/11/2023
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-41068

Human VMAT2 in complex with serotonin

EMD-41068

Single-particle
3.72 Å
EMD-41068 Deposition: 15/06/2023
Map released: 01/11/2023
Last modified: 13/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Human VMAT2 in complex with serotonin
Fitted models: 8t6b (Avg. Q-score: 0.39)

Deposition Authors: Pidathala S, Dai Y , Lee CH
Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2.
Pidathala S, Liao S, Dai Y , Li X , Long C , Chang CL , Zhang Z , Lee CH
(2023) Nature , 623 , 1086 - 1092
PUBMED: 37914936
DOI: doi:10.1038/s41586-023-06727-9
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood1. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders2. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission3-5. VMATs are also therapeutic drug targets for a number of different conditions6-9. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.