Panel A: Structure of VMAT2 with reserpine, open to the cytoplasm. Panel B: Structure of VMAT2 with tetrabenazine, completely occluded. Panel C: Structure of VMAT2 with ketanserin, open to the lumenal side. Panel D: Structure of VMAT2 with serotonin as a substrate, open to the lumenal side. Key acidic residues are shown as sticks. The structures reflect distinct conformational states and involve relative rocker switch movements of the N- and C-terminal halves of the transporter. The pathways on either side of the transporter involve membrane-spanning helices from pseudo-symmetric repeated elements, highlighted by the positions of the first helix of each repeat (TM 1 in green, TM4 in blue, TM7 in orange and TM10 yellow).
Structures of human VMAT2 reveal different inhibitor-binding profiles. Since October 2023 until the time this review was written, 25 cryo-EM structures of human VMAT2 have been deposited in the PDB (Table S1). (A–D) Structures have been determined in the presence of several inhibitors, three of them shown here: (A) reserpine, (B) TBZ, (C) ketanserin, and various substrates (D, a structure with serotonin as an example), shown as sticks. Key acidic residues are also shown as sticks (hVMAT2 numbering). The structures reflect distinct conformational states: open to the cytoplasm (A), completely occluded (B), and open to the lumenal side (C and D). Pathway opening involves relative rocker switch movements of the N- and C-terminal halves of the transporter. The pathways on either side of the transporter involve membrane-spanning helices from pseudosymmetric repeated elements, highlighted by the positions of the first helix of each repeat (TM 1 in green, TM4 in blue, TM7 in orange, and TM10 yellow). Figures created with PyMol for PDB identifiers 8T6A, 8T69, 8JT9, and 8JSW, respectively, and compiled with biorender.com (Adapted from Schuldiner and Forrest [2024]).