Eva HELLSBERG
Molecular Drug Targets
University of Vienna
Division of Pharmaceutical Chemistry
Jofes-Holaubek-Platz 2 (UZA II)
A-1090 Vienna
Website Eva Hellsberg

Program

”The molecular puzzle of the human serotonin transporter: where a proton and a potassium ion fit in the picture”

The human serotonin transporter hSERT, or SLC6A4, from the solute carrier 6 (SLC6) protein family, plays an important role in the central and peripheral nervous systems. Its major neurobiological task is the termination of serotonergic neurotransmission by reuptake of its endogenous substrate, serotonin, into presynaptic boutons after signaling. The transporter undergoes several conformational changes in each physiological substrate uptake cycle and interacts with protons, sodium, chloride, and potassium ions during these transitions. Over the years, a substantial body of knowledge about hSERT function and mechanism has been accumulated, significantly improving pharmacological treatment options especially for major depression by covering several chemical compound classes. Nevertheless, effective symptom amelioration, side effect profiles, and patient compliance are still far from ideal and require urgent action. For this reason, a fundamental approach is to tackle key unanswered questions regarding the transporter’s function, including the mechanism of potassium and proton binding, whose roles are both interconnected and poorly understood. To this end, we have applied molecular simulation approaches at the coarse-grained and fully-atomistic levels, including free energy calculations. The simulations predict the locations of the potassium and proton binding sites and suggest the molecular origins of selectivity at each site. In addition to the gains in basic scientific understanding, the knowledge obtained paves the way for designing mechanism-based transporter ligands that are useful as highly specialized therapeutic agents.

Host: Walter SANDTNER

Contact for questions: Helmut KUBISTA