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

Mostyn, SN; Wilson, KA; Schumann-Gillett, A; Frangos, ZJ; Shimmon, S; Rawling, T; Ryan, RM; O’mara, ML; Vandenberg, RJ

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

Mostyn, SN Wilson, KA Schumann-Gillett, A Frangos, ZJ Shimmon, S Rawling, T

Ryan, RM O’mara, ML Vandenberg, RJ

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Publication Type:: Journal Article
Citation:: eLife, 2019, 8
Issue Date:: 2019-10-01

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Field	Value	Language
dc.contributor.author	Mostyn, SN	en_US
dc.contributor.author	Wilson, KA	en_US
dc.contributor.author	Schumann-Gillett, A	en_US
dc.contributor.author	Frangos, ZJ	en_US
dc.contributor.author	Shimmon, S	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Ryan, RM	en_US
dc.contributor.author	O’mara, ML	en_US
dc.contributor.author	Vandenberg, RJ https://orcid.org/0000-0003-1523-4814	en_US
dc.date.available	2019-09-30	en_US
dc.date.issued	2019-10-01	en_US
dc.identifier.citation	eLife, 2019, 8	en_US
dc.identifier.uri	http://hdl.handle.net/10453/136615
dc.description.abstract	© Mostyn et al. 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.	en_US
dc.relation.ispartof	eLife	en_US
dc.relation.isbasedon	10.7554/eLife.47150	en_US
dc.title	Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	open_access
pubs.publication-status	Published	en_US
pubs.volume	8	en_US

Abstract:

© Mostyn et al. 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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http://hdl.handle.net/10453/136615