Extended Data Fig. 7: Structural comparisons of substrate and inhibitor binding sites.

a, The displacement of substrate NA during conformational transition from outward-facing to inward-facing state. Structural comparison of NET^NA and dDAT^NA (PDB: 6M0Z) are carried out using the scaffold domain as a reference. The structures of NET^NA and dDAT^NE are colored in orange and grey, respectively. (inset) Substrate NA molecules are shown as spheres and sticks. Key residues involved in substrate binding are represented as sticks. The displacement of substrate NA and side chains of key residues are labeled. b, Binding position comparison of bupropion, ziprasidone and ibogaine. The structures of NET^BPP and NET^ZPD are depicted as slate and green cartoon, respectively. The structure of SERT bound with ibogaine (SERT^ibogaine) in inward-facing state (PDB ID: 6DZZ) is depicted as green cartoon. Ligands are represented as spheres. c, The binding mode of bupropion. Superposition was performed between NET^BPP and SERT bound with serotonin (SERT^5-HT) in inward-facing state (PDB ID: 7LI9) based on the overall structure. NET^BPP and SERT^5-HT are colored in blue and grey, respectively. Residues surrounding the binding site are visualized as sticks. d, The binding mode of ziprasidone. Superposition was carried out between NET^ZPD and SERT^5-HT in the inward-open conformation based on the overall structure. NET^ZPD and SERT^5-HT are colored in green and grey, respectively. Residues surrounding the binding site are visualized as sticks. e, A comparative analysis of the binding modes of bupropion, ziprasidone, and ibogaine is provided, highlighting their differences of binding positions.