title: X-ray structures and mechanism of the human serotonin transporter.
abstract: The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.
authors.affiliation: Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coleman
authors.affiliation: Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Green
authors.affiliation: Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.|Howard Hughes Medical Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gouaux
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015283:Citalopram / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry; D015195:Drug Design; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D042541:Intracellular Space / Q000378:metabolism; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D017374:Paroxetine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D007140:Immunoglobulin Fab Fragments; D007477:Ions; D008024:Ligands; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D012701:Serotonin; D017374:Paroxetine