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From Proteopedia
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/SC6A4_HUMAN SC6A4_HUMAN] Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.<ref>PMID:17506858</ref> <ref>PMID:18227069</ref> <ref>PMID:19270731</ref> | [https://www.uniprot.org/uniprot/SC6A4_HUMAN SC6A4_HUMAN] Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.<ref>PMID:17506858</ref> <ref>PMID:18227069</ref> <ref>PMID:19270731</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
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| + | Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.,Singh I, Seth A, Billesbolle CB, Braz J, Rodriguiz RM, Roy K, Bekele B, Craik V, Huang XP, Boytsov D, Pogorelov VM, Lak P, O'Donnell H, Sandtner W, Irwin JJ, Roth BL, Basbaum AI, Wetsel WC, Manglik A, Shoichet BK, Rudnick G Cell. 2023 May 11;186(10):2160-2175.e17. doi: 10.1016/j.cell.2023.04.010. Epub , 2023 May 2. PMID:37137306<ref>PMID:37137306</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7txt" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
Structure of human serotonin transporter bound to small molecule '8090 in lipid nanodisc and NaCl
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Categories: Homo sapiens | Large Structures | Mus musculus | Basbaum AI | Bekele B | Billesboelle CB | Boytsov D | Braz J | Craik V | Huang XP | Lak P | Manglik A | O'Donnell H | Rodriguiz RM | Roth BL | Roy K | Rudnick G | Sandtner W | Seth A | Shoichet BK | Singh I | Wetsel WC
