Molecular basis for the dopamine reuptake and inhibition mechanism of human dopamine transporter.

Dopamine (DA) is a key neurotransmitter that regulates neuropsychological behaviors, including movement, emotion, motivation, and cognition. Dysregulation of dopaminergic signaling is linked to psychiatric and neurodegenerative disorders, including Parkinson's disease, depression, and schizophrenia. The dopamine transporter (DAT) controls DA levels by facilitating its reuptake from the synaptic cleft, terminating dopaminergic signaling. Here, we report structures of full-length human DAT (hDAT) in its apo state and in complexes with substrates and antidepressant compounds. The antidepressant compounds bupropion and vanoxerine bind to the central site of hDAT and inhibit substrate transport. Integration of structural analysis with functional assays and molecular dynamics simulations further suggests a role for potassium ions in regulating hDAT conformational transitions. Our findings reveal the molecular mechanisms governing DA reuptake and the specific ways in which hDAT interacts with antidepressant compounds. These insights provide a structural basis for the design of therapeutic agents targeting hDAT.