Figure 1
From: Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter
hsSERT substrate binding site and paroxetine chemical structure.
(a,d,e) hsSERT homology model in an outward-open state based on the dmDAT-cocaine complex (PDB ID 4XP4). (a) Side view of the solvent-accessible surface, with the S1 and S2 ligand-binding sites indicated. The protein is portrayed with cartoon helices colored orange (TM3), blue (TM8), magenta (TM10) and gray (all others). TMs 1 and 6 are foremost but not shown for clarity. Approximate membrane boundaries are represented as brown lines. (b) Chemical structure of paroxetine: ((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine). This SSRI is composed of three functional moieties: piperidine, benzodioxol and fluorophenyl rings. (c–e) Residues composing the S1 binding site. (c) Schematic of the subsite definitions for both hsSERT and LeuBAT. The equivalent residues in ggSERT are Y135, D138, S376 and S478 (in subsite A); D209, V212, A213, Y216, N217, T479 and G482 (in subsite B); and Y215, F375, F381, E533, T537 and V541 (in subsite C). The corresponding residues in dmSERT are F90, D93, S328 and S429 (in subsite A); D164, M167, G168, Y171, N172, T430 and G433 (in subsite B); and Y170, F327, F333, N484, P488 and I492 (in subsite C). Residues mutated in this study are in bold italics. (d,e) Structural model of the S1 crevice. (d) View from extracellular pathway, as indicated in (a). The three subsites, A, B and C, are separated by black dashed lines. Subsite C encompasses definitions from both Sorensen et al.14 and Wang et al.31, in which residues implicated only in the LeuBAT structure are to the left of the gray dashed line, referred to here as CW. Amino acids mutated in this study are labeled. Cartoon helices are colored as in (a), with TMs 1 and 6 colored red and green, respectively. Key groups are shown as sticks and sodium ions as spheres. (e) Same representation as (d), but viewed from the plane of the membrane. All residues that have been implicated in antagonist recognition within the hsSERT S1 pocket are displayed as sticks and labeled.
