Fig. 6: Proposed mechanism for VMAT2-mediated transport of monoamines.

Schematic representation of the alternating access transport cycle. The 7 states are derived from direct experimental structures (States 4 and 6), docking poses (States 1, 2 and 5), and AlphaFold2 prediction (States 3 and 7). For clarity, only TMs 1, 2, 7 and 8 are shown as empty tubes in color. States that are not experimentally determined are shown in faint shades. Two negative residues D399 and E312 along the translocation pathway (empty circles, non-protonated; solid circles filled with green, protonated) facilitate substrate movement by alternating protonation states. Significant conformational shifts, particularly in TM2 and TM7, triggered by TBZ (green) entrance at the luminal side induce a dead-end occluded state.