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A structural mechanism of nuclear receptor biased agonism

Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for su...

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Autores principales: Nemetchek, Michelle D., Chrisman, Ian M., Rayl, Mariah L., Voss, Andrew H., Hughes, Travis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897460/
https://www.ncbi.nlm.nih.gov/pubmed/36469765
http://dx.doi.org/10.1073/pnas.2215333119
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author Nemetchek, Michelle D.
Chrisman, Ian M.
Rayl, Mariah L.
Voss, Andrew H.
Hughes, Travis S.
author_facet Nemetchek, Michelle D.
Chrisman, Ian M.
Rayl, Mariah L.
Voss, Andrew H.
Hughes, Travis S.
author_sort Nemetchek, Michelle D.
collection PubMed
description Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for such agonist-specific effects remains unknown. Here, we show that partial agonists of the NR peroxisome proliferator-associated receptor γ (PPARγ), which induce better outcomes in mice compared to clinically utilized type II diabetes PPARγ-binding drugs thiazolidinediones (TZDs), also favor a different group of coactivator peptides than the TZDs. We find that PPARγ full agonists can also be biased relative to each other in terms of coactivator peptide binding. We find differences in coactivator–PPARγ bonding between the coactivator subgroups which allow agonists to favor one group of coactivator peptides over another, including differential bonding to a C-terminal residue of helix 4. Analysis of all available NR–coactivator structures indicates that such differential helix 4 bonding persists across other NR–coactivator complexes, providing a general structural mechanism of biased agonism for many NRs. Further work will be necessary to determine if such bias translates into altered coactivator occupancy and physiology in cells.
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spelling pubmed-98974602023-02-04 A structural mechanism of nuclear receptor biased agonism Nemetchek, Michelle D. Chrisman, Ian M. Rayl, Mariah L. Voss, Andrew H. Hughes, Travis S. Proc Natl Acad Sci U S A Biological Sciences Efforts to decrease the adverse effects of nuclear receptor (NR) drugs have yielded experimental agonists that produce better outcomes in mice. Some of these agonists have been shown to cause different, not just less intense, on-target transcriptomic effects; however, a structural explanation for such agonist-specific effects remains unknown. Here, we show that partial agonists of the NR peroxisome proliferator-associated receptor γ (PPARγ), which induce better outcomes in mice compared to clinically utilized type II diabetes PPARγ-binding drugs thiazolidinediones (TZDs), also favor a different group of coactivator peptides than the TZDs. We find that PPARγ full agonists can also be biased relative to each other in terms of coactivator peptide binding. We find differences in coactivator–PPARγ bonding between the coactivator subgroups which allow agonists to favor one group of coactivator peptides over another, including differential bonding to a C-terminal residue of helix 4. Analysis of all available NR–coactivator structures indicates that such differential helix 4 bonding persists across other NR–coactivator complexes, providing a general structural mechanism of biased agonism for many NRs. Further work will be necessary to determine if such bias translates into altered coactivator occupancy and physiology in cells. National Academy of Sciences 2022-12-05 2022-12-13 /pmc/articles/PMC9897460/ /pubmed/36469765 http://dx.doi.org/10.1073/pnas.2215333119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Nemetchek, Michelle D.
Chrisman, Ian M.
Rayl, Mariah L.
Voss, Andrew H.
Hughes, Travis S.
A structural mechanism of nuclear receptor biased agonism
title A structural mechanism of nuclear receptor biased agonism
title_full A structural mechanism of nuclear receptor biased agonism
title_fullStr A structural mechanism of nuclear receptor biased agonism
title_full_unstemmed A structural mechanism of nuclear receptor biased agonism
title_short A structural mechanism of nuclear receptor biased agonism
title_sort structural mechanism of nuclear receptor biased agonism
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897460/
https://www.ncbi.nlm.nih.gov/pubmed/36469765
http://dx.doi.org/10.1073/pnas.2215333119
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