Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.

Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conf...

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Autores principales:	Ralf C Kling, Nuska Tschammer, Harald Lanig, Timothy Clark, Peter Gmeiner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9db6f013c0b64f99ae903a1fd26a6b9c
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spelling	oai:doaj.org-article:9db6f013c0b64f99ae903a1fd26a6b9c2021-11-18T08:15:34ZActive-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.1932-620310.1371/journal.pone.0100069https://doaj.org/article/9db6f013c0b64f99ae903a1fd26a6b9c2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24932547/?tool=EBIhttps://doaj.org/toc/1932-6203Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-Gαi protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-Gαi-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy.Ralf C KlingNuska TschammerHarald LanigTimothy ClarkPeter GmeinerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e100069 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ralf C Kling Nuska Tschammer Harald Lanig Timothy Clark Peter Gmeiner Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
description	Partial agonists exhibit a submaximal capacity to enhance the coupling of one receptor to an intracellular binding partner. Although a multitude of studies have reported different ligand-specific conformations for a given receptor, little is known about the mechanism by which different receptor conformations are connected to the capacity to activate the coupling to G-proteins. We have now performed molecular-dynamics simulations employing our recently described active-state homology model of the dopamine D2 receptor-Gαi protein-complex coupled to the partial agonists aripiprazole and FAUC350, in order to understand the structural determinants of partial agonism better. We have compared our findings with our model of the D2R-Gαi-complex in the presence of the full agonist dopamine. The two partial agonists are capable of inducing different conformations of important structural motifs, including the extracellular loop regions, the binding pocket and, in particular, intracellular G-protein-binding domains. As G-protein-coupling to certain intracellular epitopes of the receptor is considered the key step of allosterically triggered nucleotide-exchange, it is tempting to assume that impaired coupling between the receptor and the G-protein caused by distinct ligand-specific conformations is a major determinant of partial agonist efficacy.
format	article
author	Ralf C Kling Nuska Tschammer Harald Lanig Timothy Clark Peter Gmeiner
author_facet	Ralf C Kling Nuska Tschammer Harald Lanig Timothy Clark Peter Gmeiner
author_sort	Ralf C Kling
title	Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
title_short	Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
title_full	Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
title_fullStr	Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
title_full_unstemmed	Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.
title_sort	active-state model of a dopamine d2 receptor-gαi complex stabilized by aripiprazole-type partial agonists.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/9db6f013c0b64f99ae903a1fd26a6b9c
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Active-state model of a dopamine D2 receptor-Gαi complex stabilized by aripiprazole-type partial agonists.

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