Distorted serotonin levels correlate to diseases such as depression and anxiety and these levels are regulated by re-uptake by presynaptic neurons via their serotonin transporters (SERT). We propose to examine the ibogaine-bound allosteric state SERT using cross-linking mass spectrometry. Rat SERT containing a single reactive Cystine at position 310 was overexpressed in insect cells, purified, and reconstituted into vesicles. Photocrosslinking studies were conducted using MTS-diazirine in the presence of ibogaine, and sites of crosslinking were identified by mass spectrometry. These studies identify distance constraints in full-length SERT and could lead to the development of more selective therapeutics that are more effective with fewer side effects than current selective serotonin reuptake inhibitors.

Crosslinking-mass spectrometric studies of the serotonin transporter in the inward-facing state:

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