Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120

Abstract The P2X7 receptor (P2X7R) for ATP is a therapeutic target for pathophysiological states including inflammation, pain management and epilepsy. This is facilitated by the predicted low side effect profile as the high concentrations of ATP required to activate the receptor are usually only fou...

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Autores principales:	Rebecca C. Allsopp, Sudad Dayl, Ralf Schmid, Richard J. Evans
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e4b325c9e8ca423abe4e714e25c558a0
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spelling	oai:doaj.org-article:e4b325c9e8ca423abe4e714e25c558a02021-12-02T12:32:37ZUnique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ1060612010.1038/s41598-017-00732-52045-2322https://doaj.org/article/e4b325c9e8ca423abe4e714e25c558a02017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00732-5https://doaj.org/toc/2045-2322Abstract The P2X7 receptor (P2X7R) for ATP is a therapeutic target for pathophysiological states including inflammation, pain management and epilepsy. This is facilitated by the predicted low side effect profile as the high concentrations of ATP required to activate the receptor are usually only found following cell damage/disease and so P2X7Rs respond to a “danger” signal and are not normally active. AZ10606120 is a selective antagonist for P2X7Rs (IC50 of ~10 nM) and ineffective at the P2X1R (at 10 μM). To determine the molecular basis of selectivity we generated a series of P2X7/1R chimeras and mutants. Two regions that are unique to the P2X7R, a loop insertion (residues 73–79) and threonine residues T90 and T94, are required for high affinity antagonist action. Point mutations ruled out an orthosteric antagonist site. Mutations and molecular modelling identified an allosteric binding site that forms at the subunit interface at the apex of the receptor. Molecular dynamics simulations indicated that unique P2X7R features regulate access of AZ10606120 to the allosteric site. The characterisation of the allosteric pocket provides a new and novel target for rational P2X7R drug development.Rebecca C. AllsoppSudad DaylRalf SchmidRichard J. EvansNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rebecca C. Allsopp Sudad Dayl Ralf Schmid Richard J. Evans Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
description	Abstract The P2X7 receptor (P2X7R) for ATP is a therapeutic target for pathophysiological states including inflammation, pain management and epilepsy. This is facilitated by the predicted low side effect profile as the high concentrations of ATP required to activate the receptor are usually only found following cell damage/disease and so P2X7Rs respond to a “danger” signal and are not normally active. AZ10606120 is a selective antagonist for P2X7Rs (IC50 of ~10 nM) and ineffective at the P2X1R (at 10 μM). To determine the molecular basis of selectivity we generated a series of P2X7/1R chimeras and mutants. Two regions that are unique to the P2X7R, a loop insertion (residues 73–79) and threonine residues T90 and T94, are required for high affinity antagonist action. Point mutations ruled out an orthosteric antagonist site. Mutations and molecular modelling identified an allosteric binding site that forms at the subunit interface at the apex of the receptor. Molecular dynamics simulations indicated that unique P2X7R features regulate access of AZ10606120 to the allosteric site. The characterisation of the allosteric pocket provides a new and novel target for rational P2X7R drug development.
format	article
author	Rebecca C. Allsopp Sudad Dayl Ralf Schmid Richard J. Evans
author_facet	Rebecca C. Allsopp Sudad Dayl Ralf Schmid Richard J. Evans
author_sort	Rebecca C. Allsopp
title	Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
title_short	Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
title_full	Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
title_fullStr	Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
title_full_unstemmed	Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
title_sort	unique residues in the atp gated human p2x7 receptor define a novel allosteric binding pocket for the selective antagonist az10606120
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e4b325c9e8ca423abe4e714e25c558a0
work_keys_str_mv	AT rebeccacallsopp uniqueresiduesintheatpgatedhumanp2x7receptordefineanovelallostericbindingpocketfortheselectiveantagonistaz10606120 AT sudaddayl uniqueresiduesintheatpgatedhumanp2x7receptordefineanovelallostericbindingpocketfortheselectiveantagonistaz10606120 AT ralfschmid uniqueresiduesintheatpgatedhumanp2x7receptordefineanovelallostericbindingpocketfortheselectiveantagonistaz10606120 AT richardjevans uniqueresiduesintheatpgatedhumanp2x7receptordefineanovelallostericbindingpocketfortheselectiveantagonistaz10606120
_version_	1718394069411954688

Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120

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