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- EMDB-8942: Cryo-EM structure of the ts2-active human serotonin transporter i... -
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Basic information
Entry | Database: EMDB / ID: EMD-8942 | |||||||||
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Title | Cryo-EM structure of the ts2-active human serotonin transporter in complex with 15B8 Fab and 8B6 ScFv bound to ibogaine | |||||||||
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Function / homology | ![]() negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / serotonin:sodium:chloride symporter activity / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / enteric nervous system development ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / Serotonin clearance from the synaptic cleft / serotonergic synapse / positive regulation of serotonin secretion / cocaine binding / serotonin:sodium:chloride symporter activity / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / enteric nervous system development / serotonin uptake / cellular response to cGMP / negative regulation of organ growth / sodium ion binding / neurotransmitter transmembrane transporter activity / conditioned place preference / monoamine transmembrane transporter activity / monoamine transport / serotonin binding / vasoconstriction / brain morphogenesis / neurotransmitter transport / antiporter activity / syntaxin-1 binding / amino acid transport / nitric-oxide synthase binding / membrane depolarization / behavioral response to cocaine / social behavior / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / monoatomic cation channel activity / positive regulation of cell cycle / response to nutrient / cellular response to retinoic acid / circadian rhythm / response to toxic substance / memory / platelet aggregation / actin filament binding / integrin binding / response to estradiol / presynaptic membrane / postsynaptic membrane / endosome membrane / response to hypoxia / neuron projection / response to xenobiotic stimulus / membrane raft / focal adhesion / synapse / positive regulation of gene expression / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.1 Å | |||||||||
![]() | Coleman JA / Yang D / Gouaux E | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Authors: Jonathan A Coleman / Dongxue Yang / Zhiyu Zhao / Po-Chao Wen / Craig Yoshioka / Emad Tajkhorshid / Eric Gouaux / ![]() Abstract: The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety ...The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition. | |||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 95.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.3 KB 22.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.4 KB | Display | ![]() |
Images | ![]() | 670.1 KB | ||
Masks | ![]() | 103 MB | ![]() | |
Others | ![]() ![]() ![]() | 95.3 MB 6.2 MB 6.2 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 701.6 KB | Display | ![]() |
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Full document | ![]() | 701.2 KB | Display | |
Data in XML | ![]() | 18.4 KB | Display | |
Data in CIF | ![]() | 23.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6dzyMC ![]() 0437C ![]() 8940C ![]() 8941C ![]() 8943C ![]() 6d9gC ![]() 6dzvC ![]() 6dzwC ![]() 6dzzC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | sharpened map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.044 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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-Additional map: unsharpened map
File | emd_8942_additional.map | ||||||||||||
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Annotation | unsharpened map | ||||||||||||
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-Half map: half map 1
File | emd_8942_half_map_1.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
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-Half map: half map 2
File | emd_8942_half_map_2.map | ||||||||||||
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Annotation | half map 2 | ||||||||||||
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Sample components
+Entire : Human serotonin transporter in complex with Fab/Fv bound to ibogaine
+Supramolecule #1: Human serotonin transporter in complex with Fab/Fv bound to ibogaine
+Supramolecule #2: serotonin transporter
+Supramolecule #3: 15B8 Fab
+Supramolecule #4: 8B6 ScFv
+Macromolecule #1: Sodium-dependent serotonin transporter
+Macromolecule #2: 15B8 antibody heavy chain
+Macromolecule #3: 15B8 antibody light chain
+Macromolecule #4: 8B6 antibody single chain
+Macromolecule #6: (5beta)-12-methoxyibogamine
+Macromolecule #7: DODECYL-BETA-D-MALTOSIDE
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |