Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.

To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses...

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Autores principales:	Henrik Keränen, Hugo Gutiérrez-de-Terán, Johan Åqvist
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7af1d254a1b04131aa9e60ba532b2119
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spelling	oai:doaj.org-article:7af1d254a1b04131aa9e60ba532b21192021-11-25T05:57:51ZStructural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.1932-620310.1371/journal.pone.0108492https://doaj.org/article/7af1d254a1b04131aa9e60ba532b21192014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0108492https://doaj.org/toc/1932-6203To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses to drug treatment. For G-protein coupled receptors systematic mutagenesis has provided the major part of functional data as structural information until recently has been very limited. For the pharmacologically important A(2A) adenosine receptor, extensive site-directed mutagenesis data on agonist and antagonist binding is available and crystal structures of both types of complexes have been determined. Here, we employ a computational strategy, based on molecular dynamics free energy simulations, to rationalize and interpret available alanine-scanning experiments for both agonist and antagonist binding to this receptor. These computer simulations show excellent agreement with the experimental data and, most importantly, reveal the molecular details behind the observed effects which are often not immediately evident from the crystal structures. The work further provides a distinct validation of the computational strategy used to assess effects of point-mutations on ligand binding. It also highlights the importance of considering not only protein-ligand interactions but also those mediated by solvent water molecules, in ligand design projects.Henrik KeränenHugo Gutiérrez-de-TeránJohan ÅqvistPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e108492 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Henrik Keränen Hugo Gutiérrez-de-Terán Johan Åqvist Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
description	To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses to drug treatment. For G-protein coupled receptors systematic mutagenesis has provided the major part of functional data as structural information until recently has been very limited. For the pharmacologically important A(2A) adenosine receptor, extensive site-directed mutagenesis data on agonist and antagonist binding is available and crystal structures of both types of complexes have been determined. Here, we employ a computational strategy, based on molecular dynamics free energy simulations, to rationalize and interpret available alanine-scanning experiments for both agonist and antagonist binding to this receptor. These computer simulations show excellent agreement with the experimental data and, most importantly, reveal the molecular details behind the observed effects which are often not immediately evident from the crystal structures. The work further provides a distinct validation of the computational strategy used to assess effects of point-mutations on ligand binding. It also highlights the importance of considering not only protein-ligand interactions but also those mediated by solvent water molecules, in ligand design projects.
format	article
author	Henrik Keränen Hugo Gutiérrez-de-Terán Johan Åqvist
author_facet	Henrik Keränen Hugo Gutiérrez-de-Terán Johan Åqvist
author_sort	Henrik Keränen
title	Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
title_short	Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
title_full	Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
title_fullStr	Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
title_full_unstemmed	Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.
title_sort	structural and energetic effects of a2a adenosine receptor mutations on agonist and antagonist binding.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7af1d254a1b04131aa9e60ba532b2119
work_keys_str_mv	AT henrikkeranen structuralandenergeticeffectsofa2aadenosinereceptormutationsonagonistandantagonistbinding AT hugogutierrezdeteran structuralandenergeticeffectsofa2aadenosinereceptormutationsonagonistandantagonistbinding AT johanaqvist structuralandenergeticeffectsofa2aadenosinereceptormutationsonagonistandantagonistbinding
_version_	1718414349401325568

Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.

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