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Cited by 301Cancer, Hypoxia, and MetabolismHemoglobin structure and functionEnzyme Structure and Function

Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor

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Scheuermann, Thomas H., Tomchick, Diana R., Machius, Mischa, Guo, Yan, Bruick, Richard K., Gardner, Kevin H.·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0808092106PMC PMC2626723
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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 HIF2α and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2α PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2α PAS-B modulates the affinity of the HIF2α: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.

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  • The discovery of the PAS-B cavity enabled rational screening and structure-based design of HIF-2-selective inhibitors, culminating in development of PT2977 (belzutifan).

    “This landmark discovery enabled rational screening and structure-based design of HIF-2–selective inhibitors, culminating in the development of PT2977 (belzutifan; WELIREG™).”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [273]

    The Results describe screening the HIF2α PAS-B cavity and optimizing selective binding compounds through structure–activity analysis. The Methods identify THS-044 as one such compound. Our copy does not establish that this work led to PT2977 (belzutifan) or document its structure-based design. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Crystallographic studies in 2009 revealed a large internal cavity within the PAS-B domain of HIF-2α capable of binding small molecules and modulating HIF-2α:ARNT heterodimerization in vitro.

    “This view changed in 2009, when crystallographic studies revealed a large internal cavity within the PAS-B domain of HIF-2α capable of binding small molecules and modulating HIF-2α:ARNT heterodimerization in vitro [273].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [273]

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Cited by

Sorted by citations

Authors
Scheuermann, T. H., Tomchick, D. R., Machius, M., Guo, Y., Bruick, R. K., & Gardner, K. H.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Departments of aBiochemistry and
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-01-13
Volume
106
Issue
2
Pages
450-455
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0808092106
PMC
PMC2626723
OpenAlex
W2164210517
Cited by
301
References
5
Citations by year
2026: 17 · 2025: 19 · 2024: 19 · 2023: 25 · 2022: 21 · 2021: 28 · 2020: 27 · 2019: 16 · 2018: 14 · 2017: 15 · 2016: 13 · 2015: 12 · 2014: 15 · 2013: 13 · 2012: 11
FWCI
5.26
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01ca095471-10)
  • National Cancer Institute (P01 CA95471, P01-CA095471, R01CA115962)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
HIF-2α, ARNT, PAS-B domain, hypoxia-inducible factor, bHLH-PAS transcription factors, heterodimer, oxygen sensing, small molecule screening, crystal structure
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Binding Sites, Humans, Ligands, Protein Binding, Protein Conformation, Crystallography, X-Ray, Dimerization, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors

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