7V7L

Crystal Structure of the Heterodimeric HIF-3a:ARNT Complex

Summary for 7V7L

• Entry DOI: 10.2210/pdb7v7l/pdb
• Descriptor: Aryl hydrocarbon receptor nuclear translocator, Hypoxia-inducible factor 3-alpha (3 entities in total)
• Functional Keywords: hypoxia-inducible factor, bhlh-pas, transcription
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 81384.34

Authors

Diao, X.,Ren, X.,Li, F.W.,Sun, X.,Wu, D. (deposition date: 2021-08-21, release date: 2022-05-18, Last modification date: 2023-11-29)

Primary citation

Diao, X.,Ye, F.,Zhang, M.,Ren, X.,Tian, X.,Lu, J.,Sun, X.,Hou, Z.,Chen, X.,Li, F.,Zhuang, J.,Ding, H.,Peng, C.,Rastinejad, F.,Luo, C.,Wu, D.
Identification of oleoylethanolamide as an endogenous ligand for HIF-3 alpha.
Nat Commun, 13:2529-2529, 2022

PubMed Abstract: Hypoxia-inducible factors (HIFs) are α/β heterodimeric transcription factors modulating cellular responses to the low oxygen condition. Among three HIF-α isoforms, HIF-3α is the least studied to date. Here we show that oleoylethanolamide (OEA), a physiological lipid known to regulate food intake and metabolism, binds selectively to HIF-3α. Through crystallographic analysis of HIF-3 α/β heterodimer in both apo and OEA-bound forms, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics (MD) simulations, and biochemical and cell-based assays, we unveil the molecular mechanism of OEA entry and binding to the PAS-B pocket of HIF-3α, and show that it leads to enhanced heterodimer stability and functional modulation of HIF-3. The identification of HIF-3α as a selective lipid sensor is consistent with recent human genetic findings linking HIF-3α with obesity, and demonstrates that endogenous metabolites can directly interact with HIF-α proteins to modulate their activities, potentially as a regulatory mechanism supplementary to the well-known oxygen-dependent HIF-α hydroxylation.

PubMed: 35534502
DOI: 10.1038/s41467-022-30338-z

Experimental method

X-RAY DIFFRACTION (2.3 Å)