Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour

Abstract ATP is an essential constitutive regulator of cardiac ryanodine receptors (RyR2), enabling small changes in cytosolic Ca2+ to trigger large changes in channel activity. With recent landmark determinations of the full structures of RyR1 (skeletal isoform) and RyR2 using cryo-EM, and identifi...

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Autores principales:	Chris Lindsay, Mano Sitsapesan, Wei Mun Chan, Elisa Venturi, William Welch, Maria Musgaard, Rebecca Sitsapesan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Ryanodine Binding RyR Channels Triphosphate Group Predicted Binding Energy Rotamer Toggle Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a9586cc41ca240059c5cc002b05afc15
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spelling	oai:doaj.org-article:a9586cc41ca240059c5cc002b05afc152021-12-02T15:08:29ZPromiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour10.1038/s41598-018-33328-82045-2322https://doaj.org/article/a9586cc41ca240059c5cc002b05afc152018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33328-8https://doaj.org/toc/2045-2322Abstract ATP is an essential constitutive regulator of cardiac ryanodine receptors (RyR2), enabling small changes in cytosolic Ca2+ to trigger large changes in channel activity. With recent landmark determinations of the full structures of RyR1 (skeletal isoform) and RyR2 using cryo-EM, and identification of the RyR1 ATP binding site, we have taken the opportunity to model the binding of fragments of ATP into RyR2 in order to investigate how the structure of the ATP site dictates the functional responses of ligands attracted there. RyR2 channel gating was assessed under voltage-clamp conditions and by [3H]ryanodine binding studies. We show that even the triphosphate (PPPi) moiety alone was capable of activating RyR2 but produced two distinct effects (activation or irreversible inactivation) that we suggest correspond to two preferred binding locations within the ATP site. Combinations of complementary fragments of ATP (Pi + ADP or PPi + AMP) could not reproduce the effects of ATP, however, the presence of adenosine prevented the inactivating PPPi effects, allowing activation similar to that of ATP. RyR2 appears to accommodate diverse types of molecules, including PPPi, deep within the ATP binding site. The most effective ligands, however, have at least three phosphate groups that are guided into place by a nucleoside.Chris LindsayMano SitsapesanWei Mun ChanElisa VenturiWilliam WelchMaria MusgaardRebecca SitsapesanNature PortfolioarticleRyanodine BindingRyR ChannelsTriphosphate GroupPredicted Binding EnergyRotamer ToggleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ryanodine Binding RyR Channels Triphosphate Group Predicted Binding Energy Rotamer Toggle Medicine R Science Q
spellingShingle	Ryanodine Binding RyR Channels Triphosphate Group Predicted Binding Energy Rotamer Toggle Medicine R Science Q Chris Lindsay Mano Sitsapesan Wei Mun Chan Elisa Venturi William Welch Maria Musgaard Rebecca Sitsapesan Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
description	Abstract ATP is an essential constitutive regulator of cardiac ryanodine receptors (RyR2), enabling small changes in cytosolic Ca2+ to trigger large changes in channel activity. With recent landmark determinations of the full structures of RyR1 (skeletal isoform) and RyR2 using cryo-EM, and identification of the RyR1 ATP binding site, we have taken the opportunity to model the binding of fragments of ATP into RyR2 in order to investigate how the structure of the ATP site dictates the functional responses of ligands attracted there. RyR2 channel gating was assessed under voltage-clamp conditions and by [3H]ryanodine binding studies. We show that even the triphosphate (PPPi) moiety alone was capable of activating RyR2 but produced two distinct effects (activation or irreversible inactivation) that we suggest correspond to two preferred binding locations within the ATP site. Combinations of complementary fragments of ATP (Pi + ADP or PPi + AMP) could not reproduce the effects of ATP, however, the presence of adenosine prevented the inactivating PPPi effects, allowing activation similar to that of ATP. RyR2 appears to accommodate diverse types of molecules, including PPPi, deep within the ATP binding site. The most effective ligands, however, have at least three phosphate groups that are guided into place by a nucleoside.
format	article
author	Chris Lindsay Mano Sitsapesan Wei Mun Chan Elisa Venturi William Welch Maria Musgaard Rebecca Sitsapesan
author_facet	Chris Lindsay Mano Sitsapesan Wei Mun Chan Elisa Venturi William Welch Maria Musgaard Rebecca Sitsapesan
author_sort	Chris Lindsay
title	Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
title_short	Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
title_full	Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
title_fullStr	Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
title_full_unstemmed	Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
title_sort	promiscuous attraction of ligands within the atp binding site of ryr2 promotes diverse gating behaviour
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/a9586cc41ca240059c5cc002b05afc15
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Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour

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