Structural basis for action by diverse antidepressants on biogenic amine transporters

Hui Wang, April Goehring, Kevin H. Wang, Aravind Penmatsa, Ryan Ressler, Eric Gouaux

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin- noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium-and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.

Original languageEnglish (US)
Pages (from-to)141-145
Number of pages5
JournalNature
Volume503
Issue number7474
DOIs
StatePublished - 2013

Fingerprint

Biogenic Amines
Antidepressive Agents
Serotonin Uptake Inhibitors
Tricyclic Antidepressive Agents
Pharmacology
Amino Acid Transport Systems
Sertraline
Sodium Chloride
Neurotransmitter Agents
Amino Acid Sequence

ASJC Scopus subject areas

  • General

Cite this

Wang, H., Goehring, A., Wang, K. H., Penmatsa, A., Ressler, R., & Gouaux, E. (2013). Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature, 503(7474), 141-145. https://doi.org/10.1038/nature12648

Structural basis for action by diverse antidepressants on biogenic amine transporters. / Wang, Hui; Goehring, April; Wang, Kevin H.; Penmatsa, Aravind; Ressler, Ryan; Gouaux, Eric.

In: Nature, Vol. 503, No. 7474, 2013, p. 141-145.

Research output: Contribution to journalArticle

Wang, H, Goehring, A, Wang, KH, Penmatsa, A, Ressler, R & Gouaux, E 2013, 'Structural basis for action by diverse antidepressants on biogenic amine transporters', Nature, vol. 503, no. 7474, pp. 141-145. https://doi.org/10.1038/nature12648
Wang, Hui ; Goehring, April ; Wang, Kevin H. ; Penmatsa, Aravind ; Ressler, Ryan ; Gouaux, Eric. / Structural basis for action by diverse antidepressants on biogenic amine transporters. In: Nature. 2013 ; Vol. 503, No. 7474. pp. 141-145.
@article{1b3a022a3ba44aba8a1f838fda36a4f9,
title = "Structural basis for action by diverse antidepressants on biogenic amine transporters",
abstract = "The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin- noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25{\%} of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium-and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.",
author = "Hui Wang and April Goehring and Wang, {Kevin H.} and Aravind Penmatsa and Ryan Ressler and Eric Gouaux",
year = "2013",
doi = "10.1038/nature12648",
language = "English (US)",
volume = "503",
pages = "141--145",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7474",

}

TY - JOUR

T1 - Structural basis for action by diverse antidepressants on biogenic amine transporters

AU - Wang, Hui

AU - Goehring, April

AU - Wang, Kevin H.

AU - Penmatsa, Aravind

AU - Ressler, Ryan

AU - Gouaux, Eric

PY - 2013

Y1 - 2013

N2 - The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin- noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium-and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.

AB - The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin- noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium-and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.

UR - http://www.scopus.com/inward/record.url?scp=84887403382&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887403382&partnerID=8YFLogxK

U2 - 10.1038/nature12648

DO - 10.1038/nature12648

M3 - Article

C2 - 24121440

AN - SCOPUS:84887403382

VL - 503

SP - 141

EP - 145

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7474

ER -