ArticleNature chemical biology2019
Bidirectional modulation of HIF-2 activity through chemical ligands.
Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
What it found
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Who cites it
62 citing papers in PubMed, 107 citations in OpenAlex.
- Time matters: circadian genetics and the molecular logic of human health and disease.Nature reviews. Genetics · 2026Review
- The role of hypoxia-inducible factors in myocardial ischaemia-reperfusion injury and cardioprotection.Nature reviews. Cardiology · 2026Review
- Juvenile hormone receptor relies on conserved domain interfaces for dimerization-dependent activity.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- One-Pot Silylation-Amination Synthesis of 3‑ACS omega · 2026Article
- Discovery of NKT2152, a Potent and Selective HIF-2α Inhibitor with Favorable Pharmacokinetic Properties.ACS medicinal chemistry letters · 2026Article
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- Context-dependent variability of HIF heterodimers influences interactions with macromolecular and small molecule partners.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting conserved domains of hypoxia-inducible factors for cancer therapy.The Journal of experimental medicine · 2026Article
- Small Molecule Regulation of CLOCK:BMAL1 DNA Binding Activity.bioRxiv : the preprint server for biology · 2026Article
- Conserved structural motifs in PAS, LOV, and CRY proteins regulate circadian rhythms and are therapeutic targets.FEBS letters · 2026Review
- Integration of circadian and hypoxia signaling via non-canonical heterodimerization.FEBS letters · 2026Review
- Review
- Discovery and characterization of a novel HIF-2α agonist for the treatment of CKD-related renal anemia.Acta pharmacologica Sinica · 2026Article
- Use of High Pressure NMR Spectroscopy to Rapidly Identify Proteins with Internal Ligand-Binding Voids.bioRxiv : the preprint server for biology · 2025Article
- Unraveling the role of HIF2α in melanoma progression and epithelial-mesenchymal transition.Scientific reports · 2025Article
- Pharmacological targeting of BMAL1 modulates circadian and immune pathways.Nature chemical biology · 2025Article
- Tuning the clock with BMAL1 ligand.Nature chemical biology · 2025Article
- The carotenoid torularhodin alleviates NAFLD by promoting Akkermanisa muniniphila-mediated adenosylcobalamin metabolism.Nature communications · 2025Article
- Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex.Nature communications · 2025Article
- Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.Nature chemical biology · 2025Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2α subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2α chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2α PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2α agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2α PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2α-ARNT heterodimerization.
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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.