Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	CONTEXT-DEPENDENT VARIABILITY OF HIF HETERODIMERS INFLUENCES INTERACTIONS WITH MACROMOLECULAR AND SMALL MOLECULE PARTNERS.
Journal, issue, pages	bioRxiv, Year 2025
Publish date	May 30, 2025
Authors	Joseph D Closson / Xingjian Xu / Meiling Zhang / Tarsisius T Tiyani / Leandro Pimentel Marcelino / Eta A Isiorho / Jason S Nagati / Joseph A Garcia / Kevin H Gardner /
PubMed Abstract	Hypoxia inducible factors (HIFs) are transcription factors that coordinate cellular responses to low oxygen levels, functioning as an α/β heterodimer which binds a short hypoxia response element ...Hypoxia inducible factors (HIFs) are transcription factors that coordinate cellular responses to low oxygen levels, functioning as an α/β heterodimer which binds a short hypoxia response element (HRE) DNA sequence. Prior studies suggest HIF/HRE complexes are augmented by the binding of additional factors nearby, but those interactions are not well understood. Here, we integrated structural and biochemical approaches to investigate several functionally relevant HIF assemblies with other protein, small molecule, and DNA partners. First, we used cryo-electron microscopy (cryo-EM) to establish HIF-1 and HIF-2 form novel "dimer-of-heterodimers" (DoHD) complexes on extended human EPO enhancer sequences, showing that one heterodimer bound at a canonical HRE site with the second binding in an inverted fashion to an HRE-adjacent sequence (HAS) 8 bp away. Consistent with ARNT PAS-B domains predominating interactions within a DoHD, we found HIF-1 and HIF-2 assemble mixed DoHD complexes on the same DNA. Second, we saw substantial variability among ligands for isolated ARNT or HIF-2α PAS-B domains to bind larger complexes: for example, the ARNT PAS-B binding KG-548 and KG-279 ligands both bound the simpler HIF-2 heterodimer but exhibited differential binding to a HIF-2 DoHD. Finally, we combined cryo-EM and hydrogen-deuterium exchange by mass spectrometry (HDX-MS) to show how HIF-1 and HIF-2 heterodimers engage the transforming acidic coiled-coil containing protein 3 (TACC3) coactivator via both ARNT and HIF-α subunits, though this was unseen in the larger DoHD. Our findings highlight the importance of both molecular context and dynamics in biomolecular complex formation, adding to the complexities of potential regulation.
External links	bioRxiv / PubMed:40502054 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.28 - 3.9 Å
Structure data	70416 9of0 EMDB-70416, PDB-9of0: Cryo-EM Structure of Human HIF-2a-ARNT Complexed on 20-bp HRE Method: EM (single particle) / Resolution: 3.6 Å 70418 9of2 EMDB-70418, PDB-9of2: Dimer of HIF-2a-ARNT Heterodimers Complexed on 51-bp HRE/HAS Method: EM (single particle) / Resolution: 3.7 Å 70443 9ofu EMDB-70443, PDB-9ofu: Dimer of HIF-1a-ARNT Heterodimers Complexed on 52-bp HRE/HAS Method: EM (single particle) / Resolution: 3.9 Å PDB-9opf: Context-Dependent Variability Of HIF Heterodimers Influences Interactions With Macromolecular And Small Molecule Partners Method: X-RAY DIFFRACTION / Resolution: 2.28 Å
Chemicals	ChemComp-HOH: WATER
Source	homo sapiens (human)
Keywords	DNA BINDING PROTEIN / Hypoxia / Complex / DNA / HRE / Nucleus / Transcription / Cancer / Dimer / Higher-ordered / PROTEIN BINDING / coiled-coiled / coactivator