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Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics

G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β(1) and β(2) adrenergic receptors...

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Autores principales: Xu, Xinyu, Shonberg, Jeremy, Kaindl, Jonas, Clark, Mary J., Stößel, Anne, Maul, Luis, Mayer, Daniel, Hübner, Harald, Hirata, Kunio, Venkatakrishnan, A. J., Dror, Ron O., Kobilka, Brian K., Sunahara, Roger K., Liu, Xiangyu, Gmeiner, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104803/
https://www.ncbi.nlm.nih.gov/pubmed/37059717
http://dx.doi.org/10.1038/s41467-023-37808-y
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author Xu, Xinyu
Shonberg, Jeremy
Kaindl, Jonas
Clark, Mary J.
Stößel, Anne
Maul, Luis
Mayer, Daniel
Hübner, Harald
Hirata, Kunio
Venkatakrishnan, A. J.
Dror, Ron O.
Kobilka, Brian K.
Sunahara, Roger K.
Liu, Xiangyu
Gmeiner, Peter
author_facet Xu, Xinyu
Shonberg, Jeremy
Kaindl, Jonas
Clark, Mary J.
Stößel, Anne
Maul, Luis
Mayer, Daniel
Hübner, Harald
Hirata, Kunio
Venkatakrishnan, A. J.
Dror, Ron O.
Kobilka, Brian K.
Sunahara, Roger K.
Liu, Xiangyu
Gmeiner, Peter
author_sort Xu, Xinyu
collection PubMed
description G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β(1) and β(2) adrenergic receptors (β(1)AR and β(2)AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β(2)AR over the β(1)AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β(2)AR, as well as a less stable binding pocket for constrained epinephrine in the β(1)AR. The differences in the amino acid sequence of the extracellular vestibule of the β(1)AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β(2)AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.
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spelling pubmed-101048032023-04-16 Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics Xu, Xinyu Shonberg, Jeremy Kaindl, Jonas Clark, Mary J. Stößel, Anne Maul, Luis Mayer, Daniel Hübner, Harald Hirata, Kunio Venkatakrishnan, A. J. Dror, Ron O. Kobilka, Brian K. Sunahara, Roger K. Liu, Xiangyu Gmeiner, Peter Nat Commun Article G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β(1) and β(2) adrenergic receptors (β(1)AR and β(2)AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β(2)AR over the β(1)AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β(2)AR, as well as a less stable binding pocket for constrained epinephrine in the β(1)AR. The differences in the amino acid sequence of the extracellular vestibule of the β(1)AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β(2)AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs. Nature Publishing Group UK 2023-04-14 /pmc/articles/PMC10104803/ /pubmed/37059717 http://dx.doi.org/10.1038/s41467-023-37808-y Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Xu, Xinyu
Shonberg, Jeremy
Kaindl, Jonas
Clark, Mary J.
Stößel, Anne
Maul, Luis
Mayer, Daniel
Hübner, Harald
Hirata, Kunio
Venkatakrishnan, A. J.
Dror, Ron O.
Kobilka, Brian K.
Sunahara, Roger K.
Liu, Xiangyu
Gmeiner, Peter
Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title_full Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title_fullStr Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title_full_unstemmed Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title_short Constrained catecholamines gain β(2)AR selectivity through allosteric effects on pocket dynamics
title_sort constrained catecholamines gain β(2)ar selectivity through allosteric effects on pocket dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104803/
https://www.ncbi.nlm.nih.gov/pubmed/37059717
http://dx.doi.org/10.1038/s41467-023-37808-y
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