Artificial ligand binding within the HIF2[alpha] PAS-B domain of the HIF2 transcription factor

Journal Article · Tue May 12 04:00:00 EDT 2009 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.0808092106· OSTI ID:1005482

Scheuermann, Thomas H; Tomchick, Diana R; Machius, Mischa; Guo, Yan; Bruick, Richard K; Gardner, Kevin H

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 HIF2{alpha} and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2{alpha} PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2{alpha} PAS-B modulates the affinity of the HIF2{alpha}: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.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1005482
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (2) ; 01, 2009 Vol. 106; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

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36 MATERIALS SCIENCE
AFFINITY
CRYSTAL STRUCTURE
HYDROCARBONS
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OXYGEN
TRANSCRIPTION FACTORS