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PMID: 19129502 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 2 ·2009-01-13 ·Pages 450-5

Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH

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.

MeSH Terms
Aryl Hydrocarbon Receptor Nuclear Translocator/chemistry,metabolism Basic Helix-Loop-Helix Transcription Factors/chemistry,metabolism Binding Sites Crystallography, X-Ray Dimerization Humans Ligands Protein Binding Protein Conformation
Chemicals
ARNT protein, human Basic Helix-Loop-Helix Transcription Factors Ligands Aryl Hydrocarbon Receptor Nuclear Translocator endothelial PAS domain-containing protein 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Scheuermann Thomas H
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Tomchick Diana R
Machius Mischa
Guo Yan
Bruick Richard K
Gardner Kevin H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0808092106
Published
2009-01-13
Epub
2009-00-07
Pages
450-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2626723
Subset
IM
Grants
NCI NIH HHS · P01 CA095471 · United States
NCI NIH HHS · R01 CA115962 · United States
NCI NIH HHS · P01 CA95471 · United States
Databases
PDB
3F1N, 3F1O, 3F1P
External Links
PubMed source DOI: 10.1073/pnas.0808092106 PMC Full Text View journal details
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