Subsites

After analysing each structure formed between LeuBAT and the therapeutic agents it was possible to divide the primary binding pocket into three subsites. The first subsite, subsite A, includes Asp24, Tyr21, Gly256 and Ser355 from TM1, TM6 and TM8 in the scaffold and bundle domains. According to the structures obtained, it is presumed that Asp24 forms salt bridges with the amine groups of most drugs. This residue is homologous to Asp98 in human SERT.

Subsite B is made of residues from TM3, TM6 and TM8 and is responsible for hydrophobic interactions between the non polar residues of LeuBAT and the hydrophobic ring of the drugs. This subsite also has a groove that accommodates the polar groups of the drug’s ring.

Subsite C is located in the extracellular vestibule and includes residues in TM6 and TM10 which allow interactions with bulky drugs and is presumed to also have a role as affinity and specifity inhibitor enhancer.

Figure 6. Superposition of SSRI (sertraline, orange), SNRI (duloxetine, cyan) and TCA (CMI, white) in the primary binding pocket of LeuBAT, viewed from extracellular side. Transmembrane helixes TM1, TM3, TM6, TM8 and TM10 are shown in red, green, blue, yellow and mgenta respectively. The key residues in the pocket are shown in sticks and have the same color as the helixes' where they locate at. The two sodium ions are shown in purple sphere. The regions circled are defined as subsites.