The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity.

Wilson, KA; Mostyn, SN; Frangos, ZJ; Shimmon, S; Rawling, T; Vandenberg, RJ; O'Mara, ML

The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity.

Wilson, KA Mostyn, SN Frangos, ZJ Shimmon, S Rawling, T

Vandenberg, RJ O'Mara, ML

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: The Journal of biological chemistry, 2021, pp. 100282
Issue Date:: 2021-01-12

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Field	Value	Language
dc.contributor.author	Wilson, KA
dc.contributor.author	Mostyn, SN
dc.contributor.author	Frangos, ZJ
dc.contributor.author	Shimmon, S
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Vandenberg, RJ
dc.contributor.author	O'Mara, ML
dc.date.accessioned	2021-03-01T04:24:09Z
dc.date.available	2021-01-08
dc.date.available	2021-03-01T04:24:09Z
dc.date.issued	2021-01-12
dc.identifier.citation	The Journal of biological chemistry, 2021, pp. 100282
dc.identifier.issn	0021-9258
dc.identifier.issn	1083-351X
dc.identifier.uri	http://hdl.handle.net/10453/146561
dc.description.abstract	The role of lipids in modulating membrane protein function is an emerging and rapidly growing area of research. The rational design of lipids that target membrane proteins for the treatment of pathological conditions is a novel extension in this field and provides a step forward in our understanding of membrane transporters. Bioactive lipids show considerable promise as analgesics for the treatment of chronic pain and bind to a high-affinity allosteric binding site on the human glycine transporter 2 (GlyT2 or SLC6A5). Here we use a combination of medicinal chemistry, electrophysiology, and computational modelling to develop a rational structure activity relationship for lipid inhibitors and demonstrate the key role of the lipid tail interactions for GlyT2 inhibition. Specifically, we examine how lipid inhibitor head group stereochemistry, tail length and double bond position promote enhanced inhibition. Overall, the L-stereoisomer is generally a better inhibitor than the D-stereoisomer, longer tail length correlates with greater potency, and the position of the double bond influences the activity of the inhibitor. We propose that the binding of the lipid inhibitor deep into the allosteric binding pocket is critical for inhibition. Furthermore, this provides insight into the mechanism of inhibition of GlyT2 and highlights how lipids can modulate the activity of membrane proteins by binding to cavities between helices. The principles identified in this work have broader implications for the development of a larger class of compounds that could target SLC6 transporters for disease treatment.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1082570
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1144429
dc.relation.ispartof	The Journal of biological chemistry
dc.relation.isbasedon	10.1016/j.jbc.2021.100282
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Biochemistry & Molecular Biology
dc.title	The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity.
dc.type	Journal Article
utslib.location.activity	United States
utslib.for	03 Chemical Sciences
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
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
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
dc.date.updated	2021-03-01T04:24:05Z
pubs.publication-status	Published

Abstract:

The role of lipids in modulating membrane protein function is an emerging and rapidly growing area of research. The rational design of lipids that target membrane proteins for the treatment of pathological conditions is a novel extension in this field and provides a step forward in our understanding of membrane transporters. Bioactive lipids show considerable promise as analgesics for the treatment of chronic pain and bind to a high-affinity allosteric binding site on the human glycine transporter 2 (GlyT2 or SLC6A5). Here we use a combination of medicinal chemistry, electrophysiology, and computational modelling to develop a rational structure activity relationship for lipid inhibitors and demonstrate the key role of the lipid tail interactions for GlyT2 inhibition. Specifically, we examine how lipid inhibitor head group stereochemistry, tail length and double bond position promote enhanced inhibition. Overall, the L-stereoisomer is generally a better inhibitor than the D-stereoisomer, longer tail length correlates with greater potency, and the position of the double bond influences the activity of the inhibitor. We propose that the binding of the lipid inhibitor deep into the allosteric binding pocket is critical for inhibition. Furthermore, this provides insight into the mechanism of inhibition of GlyT2 and highlights how lipids can modulate the activity of membrane proteins by binding to cavities between helices. The principles identified in this work have broader implications for the development of a larger class of compounds that could target SLC6 transporters for disease treatment.

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http://hdl.handle.net/10453/146561