Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Bidirectional modulation of HIF-2 activity through chemical ligands

Journal Article · · Nature Chemical Biology
; ; ; ; ; ; ; ; ; ;
Hypoxia-inducible factor-2 (HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive HIF-2 alpha subunit and its obligate partner subunit ARNT. Enhanced HIF-2 activity drives some cancers, whereas reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. Here, we explored HIF-2 alpha chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. We found chemically unrelated antagonists to employ the same mechanism of action. Their binding displaced residue M252 from inside the HIF-2 alpha PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2 alpha agonists and found that they significantly displaced pocket residue Y281. Its dramatic side chain movement increases heterodimerization stability and transcriptional activity. Our findings show that despite binding to the same HIF-2 alpha PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to allosterically alter HIF-2 alpha-ARNT heterodimerization.
Research Organization:
Argonne National Laboratory (ANL)
Sponsoring Organization:
USDOE Office of Science - Office of Biological and Environmental Research; National Institutes of Health (NIH); Shandong University; National Natural Science Foundation of China; National Natural Science Foundation of Jiangsu Province; Wellcome Trust; U.S. Army Research Laboratory
DOE Contract Number:
AC02-06CH11357
OSTI ID:
1514883
Journal Information:
Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 4 Vol. 15; ISSN 1552-4450
Country of Publication:
United States
Language:
English

References (50)

COSMIC: exploring the world's knowledge of somatic mutations in human cancer journal October 2014
Exactly the Same but Different: Promiscuity and Diversity in the Molecular Mechanisms of Action of the Aryl Hydrocarbon (Dioxin) Receptor journal September 2011
FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor journal June 2002
A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma journal September 2016
Structural integration in hypoxia-inducible factors journal August 2015
Structure and Signaling Mechanism of Per-ARNT-Sim Domains journal October 2009
Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia journal April 2018
Features and development of Coot journal March 2010
HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond journal December 2015
Minimizing Back Exchange in the Hydrogen Exchange-Mass Spectrometry Experiment journal September 2012
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models journal September 2016
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation journal March 2010
Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions journal March 2013
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal July 2006
HIF3α: the little we know journal November 2015
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression journal December 2011
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Phaser crystallographic software journal July 2007
Fragment-based approaches to enzyme inhibition journal December 2007
Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients journal October 2015
High resolution, high-throughput amide deuterium exchange-mass spectrometry (DXMS) determination of protein binding site structure and dynamics: Utility in pharmaceutical design journal January 2001
Allosteric inhibition of hypoxia inducible factor-2 with small molecules journal February 2013
Hypoxia-Inducible Factor Stabilizers: a New Avenue for Reducing BP While Helping Hemoglobin? journal February 2016
Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor journal January 2009
Mechanism of Intracellular cAMP Sensor Epac2 Activation: cAMP-INDUCED CONFORMATIONAL CHANGES IDENTIFIED BY AMIDE HYDROGEN/DEUTERIUM EXCHANGE MASS SPECTROMETRY (DXMS) journal March 2011
New Treatment Approaches for the Anemia of CKD journal January 2016
Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation journal April 2001
NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors journal October 2016
Structural Insights into Fibrinogen Dynamics Using Amide Hydrogen/Deuterium Exchange Mass Spectrometry journal July 2013
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch journal February 2002
Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease journal November 2016
Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2 journal July 2015
Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor journal February 2013
Targeting renal cell carcinoma with a HIF-2 antagonist journal September 2016
Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD journal June 2017
A Novel Hypoxia-Inducible Factor−Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial journal June 2016
A CTIVATION OF THE A RYL H YDROCARBON R ECEPTOR BY S TRUCTURALLY D IVERSE E XOGENOUS AND E NDOGENOUS C HEMICALS journal April 2003
Affinity selection-mass spectrometry screening techniques for small molecule drug discovery journal October 2007
HIF-1  binding to VHL is regulated by stimulus-sensitive proline hydroxylation journal August 2001
Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules journal December 2012
Principles of Ligand Binding within a Completely Buried Cavity in HIF2α PAS-B
  • Key, Jason; Scheuermann, Thomas H.; Anderson, Peter C.
  • Journal of the American Chemical Society, Vol. 131, Issue 48, p. 17647-17654 https://doi.org/10.1021/ja9073062
journal December 2009
Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics journal March 2010
Structural characterization of mammalian bHLH-PAS transcription factors journal April 2017
Identification of Cys255 in HIF-1α as a novel site for development of covalent inhibitors of HIF-1α/ARNT PasB domain protein-protein interaction journal November 2012
The HIF pathway as a therapeutic target journal August 2004
HIFalpha Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing journal April 2001
Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3α journal August 2015
Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate ( S )-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H -inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385) journal October 2018
Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials journal January 2017
Hypoxia-Inducible Factors: Master Regulators of Cancer Progression journal December 2016

Similar Records

Structural integration in hypoxia-inducible factors
Journal Article · Thu Aug 20 00:00:00 EDT 2015 · Nature (London) · OSTI ID:1248028
Identification of Cys255 in HIF-1α as a novel site for development of covalent inhibitors of HIF-1α/ARNT PasB domain protein-protein interaction
Journal Article · Thu Nov 08 23:00:00 EST 2012 · Protein Science · OSTI ID:1064490
Principles of Ligand Binding within a Completely Buried Cavity in HIF2[alpha] PAS-B
Journal Article · Mon Apr 19 00:00:00 EDT 2010 · J. Am. Chem. Soc. · OSTI ID:1006095

Related Subjects