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Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics

The treatment of chronic pain is poorly managed by current analgesics, and there is a need for new classes of drugs. We recently developed a series of bioactive lipids that inhibit the human glycine transporter GlyT2 (SLC6A5) and provide analgesia in animal models of pain. Here, we have used functio...

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Autores principales: Mostyn, Shannon N, Wilson, Katie A, Schumann-Gillett, Alexandra, Frangos, Zachary J, Shimmon, Susan, Rawling, Tristan, Ryan, Renae M, O'Mara, Megan L, Vandenberg, Robert J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797481/
https://www.ncbi.nlm.nih.gov/pubmed/31621581
http://dx.doi.org/10.7554/eLife.47150
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author Mostyn, Shannon N
Wilson, Katie A
Schumann-Gillett, Alexandra
Frangos, Zachary J
Shimmon, Susan
Rawling, Tristan
Ryan, Renae M
O'Mara, Megan L
Vandenberg, Robert J
author_facet Mostyn, Shannon N
Wilson, Katie A
Schumann-Gillett, Alexandra
Frangos, Zachary J
Shimmon, Susan
Rawling, Tristan
Ryan, Renae M
O'Mara, Megan L
Vandenberg, Robert J
author_sort Mostyn, Shannon N
collection PubMed
description The treatment of chronic pain is poorly managed by current analgesics, and there is a need for new classes of drugs. We recently developed a series of bioactive lipids that inhibit the human glycine transporter GlyT2 (SLC6A5) and provide analgesia in animal models of pain. Here, we have used functional analysis of mutant transporters combined with molecular dynamics simulations of lipid-transporter interactions to understand how these bioactive lipids interact with GlyT2. This study identifies a novel extracellular allosteric modulator site formed by a crevice between transmembrane domains 5, 7, and 8, and extracellular loop 4 of GlyT2. Knowledge of this site could be exploited further in the development of drugs to treat pain, and to identify other allosteric modulators of the SLC6 family of transporters.
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spelling pubmed-67974812019-10-21 Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics Mostyn, Shannon N Wilson, Katie A Schumann-Gillett, Alexandra Frangos, Zachary J Shimmon, Susan Rawling, Tristan Ryan, Renae M O'Mara, Megan L Vandenberg, Robert J eLife Biochemistry and Chemical Biology The treatment of chronic pain is poorly managed by current analgesics, and there is a need for new classes of drugs. We recently developed a series of bioactive lipids that inhibit the human glycine transporter GlyT2 (SLC6A5) and provide analgesia in animal models of pain. Here, we have used functional analysis of mutant transporters combined with molecular dynamics simulations of lipid-transporter interactions to understand how these bioactive lipids interact with GlyT2. This study identifies a novel extracellular allosteric modulator site formed by a crevice between transmembrane domains 5, 7, and 8, and extracellular loop 4 of GlyT2. Knowledge of this site could be exploited further in the development of drugs to treat pain, and to identify other allosteric modulators of the SLC6 family of transporters. eLife Sciences Publications, Ltd 2019-10-17 /pmc/articles/PMC6797481/ /pubmed/31621581 http://dx.doi.org/10.7554/eLife.47150 Text en © 2019, Mostyn et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Mostyn, Shannon N
Wilson, Katie A
Schumann-Gillett, Alexandra
Frangos, Zachary J
Shimmon, Susan
Rawling, Tristan
Ryan, Renae M
O'Mara, Megan L
Vandenberg, Robert J
Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title_full Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title_fullStr Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title_full_unstemmed Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title_short Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics
title_sort identification of an allosteric binding site on the human glycine transporter, glyt2, for bioactive lipid analgesics
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797481/
https://www.ncbi.nlm.nih.gov/pubmed/31621581
http://dx.doi.org/10.7554/eLife.47150
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