Δ13 LeuBAT-SSRI complexes

Four structures of Δ13 LeuBAT-SSRI complexes were determined using sertraline, paroxetine, fluoxetine and fluvoxamine. Sertraline occupies the primary binding pocket surrounded by TM1, TM3, TM6 and TM8. The amine group of the therapeutic agents forms salt bridges with the carboxyl group of Asp24 and Phe253 of LeuBAT. The tetrahydronaphthalene ring hydrophobically interacts with Tyr21 and is sandwiched between Val104, Try108 and Phe259 (figure 3a). The two chlorine atoms of the dichlorophenyl ring located in the cave interact with Pro101, Val104, Ala105, Ser356 and Gly359 through van der Waals interactions. These interactions contribute to binding of sertraline to LeuBAT and human SERT. The other SSRIs use bind in different ways. The amine group of paroxetine (figure 3b) forms hydrogen bonds with Tyr21 and Ala22 and while in fluvoxamine (figure 3d) the amine group forms hydrogen bonds with Tyr21, Ala22 and Phe253. However, the amine group of fluoxetine (figure 3c) forms no hydrogen bonds with any of the residues. The benzodioxol group of paroxetine and trifluoromethylphenyl rings from fluoxetine and fluvoxamine insert to the same cave as the chlorophenyl ring of sertraline, forming hydrophobic interactions with Val104, Tyr108 and Phe259, and van der waals forces with the carboxyl groups of Pro101, Ala105, Ser356 and Gly359. Moreover, the fluorophenyl ring of paroxetine, the phenyl ring of fluoxetine and the ether chain of fluvoxamine extend into the extracellular vestibule, forming hydrophobic and van der Waals interactions with Tyr107, Phe253, Asp404 and Thr408.

A

B

C

D

Figure 3. SSRIs share similar binding features. Transmembrane helixes TM1, TM3, TM6, TM8 and TM10 are shown in red, green, blue, yellow and magenta separately. (a) Sertraline binding site in the D13 LeuBAT mutant, viewed from extracellular site with sertraline 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. (b) Paroxetine (cyan stick) in the primary binding pocket of the D13 LeuBAT. (c) Fluoxetine (cyan stick) in the primary binding pocket of the D13 LeuBAT. (d) Fluvoxamine (cyan stick) in the primary binding pocket of the D13 LeuBAT.

SSRIs:

sertraline

 paroxetine

fluoxetine

fluvoxamine