A putative three-dimensional arrangement of the human serotonin transporter transmembrane helices: a tool to aid experimental studies.

The human serotonin transporter is the molecular target for selective serotonin reuptake inhibitor drugs which are being used for treatment of depression. A three-dimensional model of the membrane spanning parts of the transporter was constructed. The transporter was assumed to consist of 12 transmembrane alpha-helices. The model was based on published experimental data of cocaine binding to mutant transporters, amino acid sequence analysis, and interactive molecular graphics. The model suggests that a high affinity cocaine binding site is situated in a region of the model where Asp98 acts like an anchor, while a putative low affinity site is situated in another region with Glu508 as the anchoring amino acid. A series of docking experiments with various reuptake inhibitors were conducted, using interactive molecular graphics techniques combined with energy calculations and analysis of the transporter-ligand complexes. Experiments involving molecular mapping of ligand binding areas may benefit from using the current model in experimental design. From the current model, several amino acids were proposed as prime candidates for mutagenesis and subsequent ligand binding studies. Also for evaluation of results from site directed mutagenesis experiments with SERT and similar transporters we assume the model will be helpful.