Structural basis for action by diverse antidepressants on biogenic amine transporters

The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents that include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)(1...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Hui, Goehring, April, Wang, Kevin H, Penmatsa, Aravind, Ressler, Ryan, Gouaux, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/
https://www.ncbi.nlm.nih.gov/pubmed/24121440
http://dx.doi.org/10.1038/nature12648
_version_ 1782301222077726720
author Wang, Hui
Goehring, April
Wang, Kevin H
Penmatsa, Aravind
Ressler, Ryan
Gouaux, Eric
author_facet Wang, Hui
Goehring, April
Wang, Kevin H
Penmatsa, Aravind
Ressler, Ryan
Gouaux, Eric
author_sort Wang, Hui
collection PubMed
description The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents that include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)(1, 2). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homolog of BATs and has proven a valuable paradigm for understanding relationships between structure and function in BATs(3). However, because LeuT has only ~20% amino acid sequence identity to BATs and is a promiscuous amino acid transporter(4), it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT(5-7) and act as non-competitive inhibitors of transport(5). In contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket(8-16). Here, we engineered LeuT to harbor 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 TM3, 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.
format Online
Article
Text
id pubmed-3904662
institution National Center for Biotechnology Information
language English
publishDate 2013
record_format MEDLINE/PubMed
spelling pubmed-39046622014-05-07 Structural basis for action by diverse antidepressants on biogenic amine transporters Wang, Hui Goehring, April Wang, Kevin H Penmatsa, Aravind Ressler, Ryan Gouaux, Eric Nature Article The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents that include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs)(1, 2). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homolog of BATs and has proven a valuable paradigm for understanding relationships between structure and function in BATs(3). However, because LeuT has only ~20% amino acid sequence identity to BATs and is a promiscuous amino acid transporter(4), it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT(5-7) and act as non-competitive inhibitors of transport(5). In contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket(8-16). Here, we engineered LeuT to harbor 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 TM3, 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. 2013-10-13 2013-11-07 /pmc/articles/PMC3904662/ /pubmed/24121440 http://dx.doi.org/10.1038/nature12648 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wang, Hui
Goehring, April
Wang, Kevin H
Penmatsa, Aravind
Ressler, Ryan
Gouaux, Eric
Structural basis for action by diverse antidepressants on biogenic amine transporters
title Structural basis for action by diverse antidepressants on biogenic amine transporters
title_full Structural basis for action by diverse antidepressants on biogenic amine transporters
title_fullStr Structural basis for action by diverse antidepressants on biogenic amine transporters
title_full_unstemmed Structural basis for action by diverse antidepressants on biogenic amine transporters
title_short Structural basis for action by diverse antidepressants on biogenic amine transporters
title_sort structural basis for action by diverse antidepressants on biogenic amine transporters
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/
https://www.ncbi.nlm.nih.gov/pubmed/24121440
http://dx.doi.org/10.1038/nature12648
work_keys_str_mv AT wanghui structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters
AT goehringapril structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters
AT wangkevinh structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters
AT penmatsaaravind structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters
AT resslerryan structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters
AT gouauxeric structuralbasisforactionbydiverseantidepressantsonbiogenicaminetransporters