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-Structure paper
Title | Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. |
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Journal, issue, pages | Cell, Vol. 186, Issue 10, Page 2160-2175.e17, Year 2023 |
Publish date | May 11, 2023 |
Authors | Isha Singh / Anubha Seth / Christian B Billesbølle / Joao Braz / Ramona M Rodriguiz / Kasturi Roy / Bethlehem Bekele / Veronica Craik / Xi-Ping Huang / Danila Boytsov / Vladimir M Pogorelov / Parnian Lak / Henry O'Donnell / Walter Sandtner / John J Irwin / Bryan L Roth / Allan I Basbaum / William C Wetsel / Aashish Manglik / Brian K Shoichet / Gary Rudnick / |
PubMed Abstract | The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors ...The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. |
External links | Cell / PubMed:37137306 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 Å |
Structure data | EMDB-26160, PDB-7txt: |
Chemicals | ChemComp-KWC: |
Source |
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Keywords | TRANSPORT PROTEIN / Neurotransmitter transporter / small molecule / membrane protein |