Allostery of atypical modulators at oligomeric G protein-coupled receptors

Abstract Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2 muscarinic receptor, allosteric modulators regulate the binding and functional e...

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Autores principales:	Rabindra V. Shivnaraine, Brendan Kelly, Gwendolynne Elmslie, Xi-Ping Huang, Yue John Dong, Margaret Seidenberg, James W. Wells, John Ellis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/68b8f45abdf448c890100bc734c1f038
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spelling	oai:doaj.org-article:68b8f45abdf448c890100bc734c1f0382021-12-02T17:39:19ZAllostery of atypical modulators at oligomeric G protein-coupled receptors10.1038/s41598-021-88399-x2045-2322https://doaj.org/article/68b8f45abdf448c890100bc734c1f0382021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88399-xhttps://doaj.org/toc/2045-2322Abstract Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2 muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in monomers and oligomers of wild-type and mutant M2 receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2 receptor has functional consequences.Rabindra V. ShivnaraineBrendan KellyGwendolynne ElmslieXi-Ping HuangYue John DongMargaret SeidenbergJames W. WellsJohn EllisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rabindra V. Shivnaraine Brendan Kelly Gwendolynne Elmslie Xi-Ping Huang Yue John Dong Margaret Seidenberg James W. Wells John Ellis Allostery of atypical modulators at oligomeric G protein-coupled receptors
description	Abstract Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2 muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in monomers and oligomers of wild-type and mutant M2 receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2 receptor has functional consequences.
format	article
author	Rabindra V. Shivnaraine Brendan Kelly Gwendolynne Elmslie Xi-Ping Huang Yue John Dong Margaret Seidenberg James W. Wells John Ellis
author_facet	Rabindra V. Shivnaraine Brendan Kelly Gwendolynne Elmslie Xi-Ping Huang Yue John Dong Margaret Seidenberg James W. Wells John Ellis
author_sort	Rabindra V. Shivnaraine
title	Allostery of atypical modulators at oligomeric G protein-coupled receptors
title_short	Allostery of atypical modulators at oligomeric G protein-coupled receptors
title_full	Allostery of atypical modulators at oligomeric G protein-coupled receptors
title_fullStr	Allostery of atypical modulators at oligomeric G protein-coupled receptors
title_full_unstemmed	Allostery of atypical modulators at oligomeric G protein-coupled receptors
title_sort	allostery of atypical modulators at oligomeric g protein-coupled receptors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/68b8f45abdf448c890100bc734c1f038
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Allostery of atypical modulators at oligomeric G protein-coupled receptors

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