ArticlePLoS biology2009
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
Article in PLoS biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 138 citations in OpenAlex.
- Regulatory mechanism of heme-regulated inhibitor through autophosphorylation-driven activation and heme-induced deactivation.Journal of biochemistry · 2026Article
- Circadian rhythm and the molecular clock in endothelial function of the cardiovascular system.Molecular and cellular biochemistry · 2026Review
- HR3/RORα-mediated cholesterol sensing regulates TOR signaling.Nature communications · 2026Article
- Nuclear receptor protein: REV-ERB.Northern clinics of Istanbul · 2025Review
- Endothelial force sensing signals to parenchymal cells to regulate bile and plasma lipids.Science advances · 2024Article
- Oxygen is an essential gasotransmitter directly sensed via protein gasoreceptors.Animal models and experimental medicine · 2024Article
- Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBβ in Human Osteosarcoma Cell Cultures.International journal of molecular sciences · 2024Article
- Targeting NR1D1 in organ injury: challenges and prospects.Military Medical Research · 2023Review
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Oxidative stress in retinal pigment epithelium degeneration: from pathogenesis to therapeutic targets in dry age-related macular degeneration.Neural regeneration research · 2023Review
- Article
- Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB.Nature communications · 2022Article
- Melatonin inhibits osteoclastogenesis via RANKL/OPG suppression mediated by Rev-Erbα in osteoblasts.Journal of cellular and molecular medicine · 2022Article
- Regulation of protein function and degradation by heme, heme responsive motifs, and CO.Critical reviews in biochemistry and molecular biology · 2022Review
- Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ.Molecules (Basel, Switzerland) · 2021Article
- Ferric heme as a CO/NO sensor in the nuclear receptor Rev-Erbß by coupling gas binding to electron transfer.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ.Science advances · 2021Article
- Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity.International journal of molecular sciences · 2020Article
- Recent advances in modulators of circadian rhythms: an update and perspective.Journal of enzyme inhibition and medicinal chemistry · 2020Review
- Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space.Endocrine reviews · 2020Review
12 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.