Transport and inhibition mechanisms of human VMAT2.

Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, playing a vital role in monoaminergic neurotransmission 1-3 . Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders, and depression 4-6 . Suppressing VMAT2 by reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease 7,8 , respectively. Here, we describe the cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for VMAT2 transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. Moreover, the structures in three distinct states reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition, and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutics.