7TXT

Structure of human serotonin transporter bound to small molecule '8090 in lipid nanodisc and NaCl

Summary for 7TXT

• Entry DOI: 10.2210/pdb7txt/pdb
• EMDB information: 26160
• Descriptor: 15B8 Fab heavy chain, 15B8 Fab light chain, Sodium-dependent serotonin transporter, ... (4 entities in total)
• Functional Keywords: neurotransmitter transporter, small molecule, membrane protein, transport protein
• Biological source: Mus musculus; More
• Total number of polymer chains: 3
• Total formula weight: 86397.45

Authors

Singh, I.,Seth, A.,Billesboelle, C.B.,Braz, J.,Rodriguiz, R.M.,Roy, K.,Bekele, B.,Craik, V.,Huang, X.P.,Boytsov, D.,Lak, P.,O'Donnell, H.,Sandtner, W.,Roth, B.L.,Basbaum, A.I.,Wetsel, W.C.,Manglik, A.,Shoichet, B.K.,Rudnick, G. (deposition date: 2022-02-09, release date: 2023-03-15, Last modification date: 2024-11-06)

Primary citation

Singh, I.,Seth, A.,Billesbolle, C.B.,Braz, J.,Rodriguiz, R.M.,Roy, K.,Bekele, B.,Craik, V.,Huang, X.P.,Boytsov, D.,Pogorelov, V.M.,Lak, P.,O'Donnell, H.,Sandtner, W.,Irwin, J.J.,Roth, B.L.,Basbaum, A.I.,Wetsel, W.C.,Manglik, A.,Shoichet, B.K.,Rudnick, G.
Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.
Cell, 186:2160-2175.e17, 2023

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 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.

PubMed: 37137306
DOI: 10.1016/j.cell.2023.04.010

Experimental method

ELECTRON MICROSCOPY (3 Å)