Δ13 LeuBAT-TCA complex and Δ6 LeuBAT-mazindol complex

The tricyclic antidepressant CMI binds to the primary binding pocket ofΔ13 LeuBAT (figure5a), in agreement with a human SERT-TCA model. The tricyclic ring is surrounded by hydrophobic residues Tyr21, Val104, Tyr108, Phe253 and Phe259. The chlorine atom in the tricyclic ring inserts to the pocket formed by Ala105, Ser356 and Gly359, similar to the chorine positions in sertraline or the trifluoromethyl moiety in fluoxetine. In addition, the structure is consistent with interactions between Ala105 (Ala173 in SERT) and the TCA 3-position, and with Phe253 (Phe335 in SERT) being near the TCA 7-position. The structure is in harmony with the conclusion that Ser438 in human SERT (Ser355 inΔ13 LeuBAT) is near to the aminopropyl chain of TCA and the binding affinity is affected due to steric clash when S438 mutates to T438.

Δ6 LeuBAT is used for mazindol binding. The mazindol binds to the primary site and is surrounded by a hydrophobic pocket formed by Tyr21, Val104, Tyr108 and Phe259 (figure 5b). The hydroxyl group forms hydrogen bonds with the carboxyl group of Asp24 and phenol group of Tyr108. The chlorophenyl ring inserts into the groove formed by Ala105, Ser356 and Gly359, similar to sertraline. These interactions are very important in affinity binding of mazindol to SERT.

A

B

Figure 5. Transmembrane helixes TM1, TM3, TM6, TM8 and TM10 are shown in red, green, blue, yellow and magenta separately. The complexes are viewed from extracellular site with inhibitors shown as cyan sticks. Sodium ions and key residues are shown as purple star and orange sticks respectively.Hydrogen bonds, salt bridges and polar interactions are in dashed lines. (a) Clomipramine in the primary binding site of Δ13 LeuBAT. (b) Mazindol in the primary binding site of Δ6 LeuBAT.

CMI

mazindol