Strange IndiaStrange India

Biogenic monoamines, vital transmitters orchestrating neurological, endocrinal, and immunological functions1-5, are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release6,7. Harnessing proton antiport, VMATs enrich monoamines ~10,000-fold and sequester neurotoxicants to protect neurons8-10. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension, and drug addiction1,8,11-16. However, the structural mechanisms underlying these actions remain elusive. Here, we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines, the Parkinsonism-inducing MPP+, the psychostimulant amphetamine, and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, while other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favored transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket possessing polar sites for specificity and a wrist-and-fist shape for versatility. Variations of this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop novel therapeutics for neurodegenerative diseases and substance abuse.

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