3F1N: Crystal structure of a high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains, with internally bound ethylene glycol

Citation:
Abstract
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.
PDB ID: 3F1NDownload
MMDB ID: 69178
PDB Deposition Date: 2008/10/28
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.479  Å
Source Organism:
Similar Structures:
Biological Unit for 3F1N: dimeric; determined by author and by software (PISA)
Molecular Components in 3F1N
Label Count Molecule
Proteins (2 molecules)
1
Endothelial PAS Domain-containing Protein 1(Gene symbol: EPAS1)
Molecule annotation
1
Aryl Hydrocarbon Receptor Nuclear Translocator(Gene symbol: ARNT)
Molecule annotation
Chemicals (3 molecules)
1
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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