The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
Heme is a ligand for the human nuclear receptors (NR) REV-ERBalpha and REV-ERBbeta, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcript...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2009
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/d76afef7ed9440828f6f21f6b78d7b15 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:d76afef7ed9440828f6f21f6b78d7b15 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:d76afef7ed9440828f6f21f6b78d7b152021-11-25T05:33:47ZThe structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.1544-91731545-788510.1371/journal.pbio.1000043https://doaj.org/article/d76afef7ed9440828f6f21f6b78d7b152009-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19243223/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Heme is a ligand for the human nuclear receptors (NR) REV-ERBalpha and REV-ERBbeta, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 A crystal structure of the REV-ERBbeta LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBbeta complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions.Keith I PardeeXiaohui XuJeff ReinkingAnja SchuetzAiping DongSuya LiuRongguang ZhangJens TiefenbachGilles LajoieAlexander N PlotnikovAlexey BotchkarevHenry M KrauseAled EdwardsPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 2, p e43 (2009) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Biology (General) QH301-705.5 |
| spellingShingle |
Biology (General) QH301-705.5 Keith I Pardee Xiaohui Xu Jeff Reinking Anja Schuetz Aiping Dong Suya Liu Rongguang Zhang Jens Tiefenbach Gilles Lajoie Alexander N Plotnikov Alexey Botchkarev Henry M Krause Aled Edwards The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| description |
Heme is a ligand for the human nuclear receptors (NR) REV-ERBalpha and REV-ERBbeta, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 A crystal structure of the REV-ERBbeta LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBbeta complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions. |
| format |
article |
| author |
Keith I Pardee Xiaohui Xu Jeff Reinking Anja Schuetz Aiping Dong Suya Liu Rongguang Zhang Jens Tiefenbach Gilles Lajoie Alexander N Plotnikov Alexey Botchkarev Henry M Krause Aled Edwards |
| author_facet |
Keith I Pardee Xiaohui Xu Jeff Reinking Anja Schuetz Aiping Dong Suya Liu Rongguang Zhang Jens Tiefenbach Gilles Lajoie Alexander N Plotnikov Alexey Botchkarev Henry M Krause Aled Edwards |
| author_sort |
Keith I Pardee |
| title |
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| title_short |
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| title_full |
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| title_fullStr |
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| title_full_unstemmed |
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. |
| title_sort |
structural basis of gas-responsive transcription by the human nuclear hormone receptor rev-erbbeta. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/d76afef7ed9440828f6f21f6b78d7b15 |
| work_keys_str_mv |
AT keithipardee thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT xiaohuixu thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT jeffreinking thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT anjaschuetz thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT aipingdong thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT suyaliu thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT rongguangzhang thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT jenstiefenbach thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT gilleslajoie thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alexandernplotnikov thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alexeybotchkarev thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT henrymkrause thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alededwards thestructuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT keithipardee structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT xiaohuixu structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT jeffreinking structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT anjaschuetz structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT aipingdong structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT suyaliu structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT rongguangzhang structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT jenstiefenbach structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT gilleslajoie structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alexandernplotnikov structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alexeybotchkarev structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT henrymkrause structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta AT alededwards structuralbasisofgasresponsivetranscriptionbythehumannuclearhormonereceptorreverbbeta |
| _version_ |
1718414607049031680 |