Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport

Jonathan A. Coleman, Dongxue Yang, Zhiyu Zhao, Po Chao Wen, Craig Yoshioka, Emad Tajkhorshid, Eric Gouaux

Research output: Contribution to journalLetter

Abstract

The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons 1–3 . Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors—small molecules that competitively block substrate binding and thereby prolong neurotransmitter action 2,4 . 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 2,3 , and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder 2,5 . 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 1,6–12 . 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 13,14 . Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors 15,16 . 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.

Original languageEnglish (US)
JournalNature
DOIs
StatePublished - Jan 1 2019

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Ibogaine
Serotonin Plasma Membrane Transport Proteins
Plasma Membrane Neurotransmitter Transport Proteins
Serotonin
Neurotransmitter Agents
Binding Sites
Norepinephrine Plasma Membrane Transport Proteins
Cryoelectron Microscopy
Amphetamines
Dopamine Plasma Membrane Transport Proteins
Competitive Binding
Serotonin Uptake Inhibitors
Recycling
Attention Deficit Disorder with Hyperactivity
Autistic Disorder
Anxiety Disorders
Biological Products
Bipolar Disorder
Cocaine
Sodium Chloride

ASJC Scopus subject areas

  • General

Cite this

Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. / Coleman, Jonathan A.; Yang, Dongxue; Zhao, Zhiyu; Wen, Po Chao; Yoshioka, Craig; Tajkhorshid, Emad; Gouaux, Eric.

In: Nature, 01.01.2019.

Research output: Contribution to journalLetter

Coleman, Jonathan A. ; Yang, Dongxue ; Zhao, Zhiyu ; Wen, Po Chao ; Yoshioka, Craig ; Tajkhorshid, Emad ; Gouaux, Eric. / Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. In: Nature. 2019.
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abstract = "The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons 1–3 . Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors—small molecules that competitively block substrate binding and thereby prolong neurotransmitter action 2,4 . 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 2,3 , and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder 2,5 . 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 1,6–12 . 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 13,14 . Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors 15,16 . 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.",
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AU - Coleman, Jonathan A.

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N2 - The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons 1–3 . Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors—small molecules that competitively block substrate binding and thereby prolong neurotransmitter action 2,4 . 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 2,3 , and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder 2,5 . 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 1,6–12 . 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 13,14 . Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors 15,16 . 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.

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