3F1N

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

Summary for 3F1N

• Entry DOI: 10.2210/pdb3f1n/pdb
• Related: 1P97 1X0O 2A24 2B02 3F1O 3F1P
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: pas domain, heterodimer, internal cavity, activator, angiogenesis, congenital erythrocytosis, developmental protein, differentiation, disease mutation, dna-binding, hydroxylation, nucleus, phosphoprotein, transcription, transcription regulation, ubl conjugation, alternative splicing, polymorphism
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q99814 P27540
• Total number of polymer chains: 2
• Total formula weight: 27967.60

Authors

Scheuermann, T.H.,Tomchick, D.R.,Machius, M.,Guo, Y.,Bruick, R.K.,Gardner, K.H. (deposition date: 2008-10-28, release date: 2009-01-20, Last modification date: 2023-09-06)

Primary citation

Scheuermann, T.H.,Tomchick, D.R.,Machius, M.,Guo, Y.,Bruick, R.K.,Gardner, K.H.
Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor.
Proc.Natl.Acad.Sci.USA, 106:450-455, 2009

PubMed 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.

PubMed: 19129502
DOI: 10.1073/pnas.0808092106

Experimental method

X-RAY DIFFRACTION (1.479 Å)