Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784882253866729472 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9897460 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT nemetchekmichelled astructuralmechanismofnuclearreceptorbiasedagonism AT chrismanianm astructuralmechanismofnuclearreceptorbiasedagonism AT raylmariahl astructuralmechanismofnuclearreceptorbiasedagonism AT vossandrewh astructuralmechanismofnuclearreceptorbiasedagonism AT hughestraviss astructuralmechanismofnuclearreceptorbiasedagonism AT nemetchekmichelled structuralmechanismofnuclearreceptorbiasedagonism AT chrismanianm structuralmechanismofnuclearreceptorbiasedagonism AT raylmariahl structuralmechanismofnuclearreceptorbiasedagonism AT vossandrewh structuralmechanismofnuclearreceptorbiasedagonism AT hughestraviss structuralmechanismofnuclearreceptorbiasedagonism |