Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport.
Journal, issue, pages	Nature, Vol. 569, Issue 7754, Page 141-145, Year 2019
Publish date	Apr 24, 2019
Authors	Jonathan A Coleman / Dongxue Yang / Zhiyu Zhao / Po-Chao Wen / Craig Yoshioka / Emad Tajkhorshid / Eric Gouaux /
PubMed 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.
External links	Nature / PubMed:31019304 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.3 - 4.8 Å
Structure data	EMDB-0437: Cryo-EM structure of the wild-type human serotonin transporter in complex with 15B8 Fab bound to noribogaine Method: EM (single particle) / Resolution: 4.8 Å 8940 6dzv EMDB-8940, PDB-6dzv: Wild type human serotonin transporter in complex with 15B8 Fab bound to ibogaine in occluded conformation Method: EM (single particle) / Resolution: 4.2 Å 8941 6dzw EMDB-8941, PDB-6dzw: Cryo-EM structure of the ts2-inactive human serotonin transporter in complex with paroxetine and 15B8 Fab and 8B6 ScFv Method: EM (single particle) / Resolution: 4.3 Å 8942 6dzy EMDB-8942, PDB-6dzy: Cryo-EM structure of the ts2-active human serotonin transporter in complex with 15B8 Fab and 8B6 ScFv bound to ibogaine Method: EM (single particle) / Resolution: 4.1 Å 8943 6dzz EMDB-8943, PDB-6dzz: Cryo-EM Structure of the wild-type human serotonin transporter in complex with ibogaine and 15B8 Fab in the inward conformation Method: EM (single particle) / Resolution: 3.6 Å PDB-6d9g: X-ray Structure of the FAB Fragment of 15B8, a Murine Monoclonal Antibody Specific for the Human Serotonin Transporter Method: X-RAY DIFFRACTION / Resolution: 2.3 Å
Chemicals	ChemComp-HOH: WATER ChemComp-HJM: (5beta)-12-methoxyibogamine / alkaloidYM ChemComp-Y01: CHOLESTEROL HEMISUCCINATE ChemComp-8PR: Paroxetine / antidepressant, inhibitorYM ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose ChemComp-LMT: DODECYL-BETA-D-MALTOSIDE / detergent*YM
Source	homo sapiens (human) mus musculus (house mouse)
Keywords	IMMUNE SYSTEM / Antibody / TRANSPORT PROTEIN/IMMUNE SYSTEM / ibogaine / human serotonin transporter / Fab / TRANSPORT PROTEIN-IMMUNE SYSTEM complex / paroxetine / antidepressant