Abstract
In spite of the important role of the human serotonin transporter (hSERT) in depression treatment, the molecular details of how antidepressant drugs bind are still not completely understood, in particular those related to potential high- and low-affinity binding sites in hSERT. Here, we utilize amber codon suppression in hSERT to encode the photo-cross-linking unnatural amino acid p-azido-l-phenylalanine into the suggested high- and low-affinity binding sites. We then employ UV-induced cross-linking with azF to map the binding site of escitalopram and paroxetine, two prototypical selective serotonin reuptake inhibitors (SSRIs). We find that the two antidepressant drugs exclusively cross-link to azF incorporated at the high-affinity binding site of hSERT, while cross-linking is not observed at the low-affinity binding site. Combined with previous homology models and recent structural data on hSERT, our results provide important information to understand the molecular details of these clinical relevant binding sites.
| Original language | English |
|---|---|
| Journal | ACS chemical biology |
| Volume | 12 |
| Issue number | 10 |
| Pages (from-to) | 2558-2562 |
| Number of pages | 5 |
| ISSN | 1554-8929 |
| DOIs | |
| Publication status | Published - 20 Oct 2017 |
Keywords
- Binding Sites
- Citalopram
- Crystallography, X-Ray
- Humans
- Models, Molecular
- Paroxetine
- Protein Binding
- Protein Conformation
- Serotonin Plasma Membrane Transport Proteins
- Serotonin Uptake Inhibitors
- Journal Article