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Exploring Ligand Binding Domain Dynamics in the NRs Superfamily

Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations...

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Autores principales: D’Arrigo, Giulia, Autiero, Ida, Gianquinto, Eleonora, Siragusa, Lydia, Baroni, Massimo, Cruciani, Gabriele, Spyrakis, Francesca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369052/
https://www.ncbi.nlm.nih.gov/pubmed/35955864
http://dx.doi.org/10.3390/ijms23158732
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author D’Arrigo, Giulia
Autiero, Ida
Gianquinto, Eleonora
Siragusa, Lydia
Baroni, Massimo
Cruciani, Gabriele
Spyrakis, Francesca
author_facet D’Arrigo, Giulia
Autiero, Ida
Gianquinto, Eleonora
Siragusa, Lydia
Baroni, Massimo
Cruciani, Gabriele
Spyrakis, Francesca
author_sort D’Arrigo, Giulia
collection PubMed
description Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations in response to substrate, agonist, and antagonist binding, leading to distinct transcription effects. A key feature of NRs is, indeed, their intrinsic dynamics that make them a challenging target in drug discovery. This work aims to provide a meaningful investigation of NR structural variability to outline a dynamic profile for each of them. To do that, we propose a methodology based on the computation and comparison of protein cavities among the crystallographic structures of NR LBDs. First, pockets were detected with the FLAPsite algorithm and then an “all against all” approach was applied by comparing each pair of pockets within the same sub-family on the basis of their similarity score. The analysis concerned all the detectable cavities in NRs, with particular attention paid to the active site pockets. This approach can guide the investigation of NR intrinsic dynamics, the selection of reference structures to be used in drug design and the easy identification of alternative binding sites.
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spelling pubmed-93690522022-08-12 Exploring Ligand Binding Domain Dynamics in the NRs Superfamily D’Arrigo, Giulia Autiero, Ida Gianquinto, Eleonora Siragusa, Lydia Baroni, Massimo Cruciani, Gabriele Spyrakis, Francesca Int J Mol Sci Article Nuclear receptors (NRs) are transcription factors that play an important role in multiple diseases, such as cancer, inflammation, and metabolic disorders. They share a common structural organization composed of five domains, of which the ligand-binding domain (LBD) can adopt different conformations in response to substrate, agonist, and antagonist binding, leading to distinct transcription effects. A key feature of NRs is, indeed, their intrinsic dynamics that make them a challenging target in drug discovery. This work aims to provide a meaningful investigation of NR structural variability to outline a dynamic profile for each of them. To do that, we propose a methodology based on the computation and comparison of protein cavities among the crystallographic structures of NR LBDs. First, pockets were detected with the FLAPsite algorithm and then an “all against all” approach was applied by comparing each pair of pockets within the same sub-family on the basis of their similarity score. The analysis concerned all the detectable cavities in NRs, with particular attention paid to the active site pockets. This approach can guide the investigation of NR intrinsic dynamics, the selection of reference structures to be used in drug design and the easy identification of alternative binding sites. MDPI 2022-08-05 /pmc/articles/PMC9369052/ /pubmed/35955864 http://dx.doi.org/10.3390/ijms23158732 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
D’Arrigo, Giulia
Autiero, Ida
Gianquinto, Eleonora
Siragusa, Lydia
Baroni, Massimo
Cruciani, Gabriele
Spyrakis, Francesca
Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title_full Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title_fullStr Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title_full_unstemmed Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title_short Exploring Ligand Binding Domain Dynamics in the NRs Superfamily
title_sort exploring ligand binding domain dynamics in the nrs superfamily
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369052/
https://www.ncbi.nlm.nih.gov/pubmed/35955864
http://dx.doi.org/10.3390/ijms23158732
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