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Distinct Conformations of Mirabegron Determined by MicroED

Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug and what conformational changes it may undergo upon binding its receptor remain unknown. In this study, we employed micr...

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Autores principales: Lin, Jieye, Unge, Johan, Gonen, Tamir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326998/
https://www.ncbi.nlm.nih.gov/pubmed/37425799
http://dx.doi.org/10.1101/2023.06.28.546957
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author Lin, Jieye
Unge, Johan
Gonen, Tamir
author_facet Lin, Jieye
Unge, Johan
Gonen, Tamir
author_sort Lin, Jieye
collection PubMed
description Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug and what conformational changes it may undergo upon binding its receptor remain unknown. In this study, we employed microcrystal electron diffraction (MicroED) to reveal its elusive three-dimensional (3D) structure. We find that the drug adopts two distinct conformational states (conformers) within the asymmetric unit. Analysis of hydrogen bonding and packing demonstrated that the hydrophilic groups were embedded within the crystal lattice, resulting in a hydrophobic surface and low water solubility. Structural comparison revealed the presence of trans- and cis- forms in conformers 1 and 2, respectively. Comparison of the structures of Mirabegron alone with that of the drug bound to its receptor,(1) the beta 3 adrenergic receptor (β3AR) suggests that the drug undergoes major conformational change to fit in the receptor agonist binding site. This research highlights the efficacy of MicroED in determining the unknown and polymorphic structures of active pharmaceutical ingredients (APIs) directly from powders.
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spelling pubmed-103269982023-07-08 Distinct Conformations of Mirabegron Determined by MicroED Lin, Jieye Unge, Johan Gonen, Tamir bioRxiv Article Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug and what conformational changes it may undergo upon binding its receptor remain unknown. In this study, we employed microcrystal electron diffraction (MicroED) to reveal its elusive three-dimensional (3D) structure. We find that the drug adopts two distinct conformational states (conformers) within the asymmetric unit. Analysis of hydrogen bonding and packing demonstrated that the hydrophilic groups were embedded within the crystal lattice, resulting in a hydrophobic surface and low water solubility. Structural comparison revealed the presence of trans- and cis- forms in conformers 1 and 2, respectively. Comparison of the structures of Mirabegron alone with that of the drug bound to its receptor,(1) the beta 3 adrenergic receptor (β3AR) suggests that the drug undergoes major conformational change to fit in the receptor agonist binding site. This research highlights the efficacy of MicroED in determining the unknown and polymorphic structures of active pharmaceutical ingredients (APIs) directly from powders. Cold Spring Harbor Laboratory 2023-06-28 /pmc/articles/PMC10326998/ /pubmed/37425799 http://dx.doi.org/10.1101/2023.06.28.546957 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Lin, Jieye
Unge, Johan
Gonen, Tamir
Distinct Conformations of Mirabegron Determined by MicroED
title Distinct Conformations of Mirabegron Determined by MicroED
title_full Distinct Conformations of Mirabegron Determined by MicroED
title_fullStr Distinct Conformations of Mirabegron Determined by MicroED
title_full_unstemmed Distinct Conformations of Mirabegron Determined by MicroED
title_short Distinct Conformations of Mirabegron Determined by MicroED
title_sort distinct conformations of mirabegron determined by microed
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326998/
https://www.ncbi.nlm.nih.gov/pubmed/37425799
http://dx.doi.org/10.1101/2023.06.28.546957
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