Structural insights into vesicular monoamine storage and drug interactions

Jin Ye, Huaping Chen, Kaituo Wang, Yi Wang, Aaron Ammerman, Samjhana Awasthi, Jinbin Xu, Bin Liu () and Weikai Li ()
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Jin Ye: Washington University School of Medicine
Huaping Chen: Washington University School of Medicine
Kaituo Wang: University of Copenhagen
Yi Wang: Washington University School of Medicine
Aaron Ammerman: Washington University School of Medicine
Samjhana Awasthi: Washington University School of Medicine
Jinbin Xu: Washington University School of Medicine
Bin Liu: University of Minnesota
Weikai Li: Washington University School of Medicine

Nature, 2024, vol. 629, issue 8010, 235-243

Abstract: Abstract 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 around 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 unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP+, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured 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 that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in 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 therapeutics for neurodegenerative diseases and substance abuse.

Date: 2024
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DOI: 10.1038/s41586-024-07290-7

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