The hypoxia-inducible factor (HIF) basic helix-loop-helix Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (bHLH-PAS) transcription factors are master regulators of the conserved molecular mechanism by which metazoans sense and respond to reductions in local oxygen concentrations. In humans, HIF is critically important for the sustained growth and metastasis of solid tumors. Here, we describe crystal structures of the heterodimer formed by the C-terminal PAS domains from the HIF2alpha and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2alpha PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2alpha PAS-B modulates the affinity of the HIF2alpha:ARNT PAS-B heterodimer in vitro. Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626723 | PMC |
| http://dx.doi.org/10.1073/pnas.0808092106 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B.
Protein Sci
November 2024
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
While transcription factors have been generally perceived as "undruggable," an exception is the HIF-2 hypoxia-inducible transcription factor, which contains an internal cavity that is sufficiently large to accommodate a range of small-molecules, including the therapeutically used inhibitor belzutifan. Given the relatively long ligand residence times of these small molecules and the lack of any experimentally observed pathway connecting the cavity to solvent, there has been great interest in understanding how these drug ligands exit the buried receptor cavity. Here, we focus on the relevant PAS-B domain of hypoxia-inducible factor 2α (HIF-2α) and examine how one such small molecule (THS-017) exits from the buried cavity within this domain on the seconds-timescale using atomistic simulations and ZZ-exchange NMR.
View Article and Find Full Text PDFMolecular Dynamics Reveals Altered Interactions between Belzutifan and HIF-2 with Natural Variant G323E or Proximal Phosphorylation at T324.
ACS Omega
September 2024
School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
In patients with von-Hippel Lindau (VHL) disease, hypoxia-independent accumulation of HIF-2α leads to increased transcriptional activity of HIF-2α:ARNT that drives cancers such as renal cell carcinoma. Belzutifan, a recently FDA-approved drug, is designed to prevent the transcriptional activity of HIF-2α:ARNT, thereby overcoming the consequences of its unnatural accumulation in VHL-dependent cancers. Emerging evidence suggests that the naturally occurring variant G323E located in the HIF-2α drug binding pocket prevents inhibitory activity of belzutifan analogs, though the mechanism of inhibition remains unclear.
View Article and Find Full Text PDFNRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes.
Int J Biol Sci
August 2024
Department of Cardiology of The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1.
View Article and Find Full Text PDFIdentification of small-molecule ligand-binding sites on and in the ARNT PAS-B domain.
J Biol Chem
September 2024
Structural Biology Initiative, CUNY Advanced Science Research Center, New York, New York, USA; Department of Chemistry and Biochemistry, City College of New York, New York, New York, USA; PhD. Programs in Biochemistry, Chemistry and Biology, The Graduate Center, CUNY, New York, New York, USA. Electronic address:
Transcription factors are challenging to target with small-molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include naturally ligand-regulated transcription factors, including our prior work with the hypoxia-inducible factor (HIF)-2 transcription factor, showing that small-molecule binding within an internal pocket of the HIF-2α Per-Aryl hydrocarbon Receptor Nuclear Translocator (ARNT)-Sim (PAS)-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to modulate several ARNT-mediated signaling pathways.
View Article and Find Full Text PDFTranscription factors are generally challenging to target with small molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include several naturally ligand-regulated transcription factors, including our prior work with the heterodimeric HIF-2 transcription factor which showed that small molecule binding within an internal pocket of the HIF-2α PAS-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of similarly targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to simultaneously modulate several ARNT-mediated signaling pathways.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!