Related Experiment Video

Updated: Jan 18, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6

Guido J M Oerlemans1, Maxime C M van den Oetelaar1, Siebe P van den Elzen1

  • 1Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Technische Universiteit Eindhoven, 5612 AZ Eindhoven, The Netherlands.

ACS Chemical Biology
|September 10, 2025
PubMed

Insights

Nuclear Receptor NR2F6 is a cancer immunotherapy target. Researchers elucidated its structure, revealing an autorepressed conformation and identifying covalent probes that inhibit coregulator recruitment, paving the way for novel cancer therapeutics.

Area of Science:

  • Molecular biology
  • Structural biology
  • Cancer research

Background:

  • The orphan nuclear receptor NR2F6 is a key target in cancer immunotherapy due to its roles in tumor growth and immune suppression.
  • Targeting NR2F6 offers a novel strategy for cancer treatment, but lacks molecular tools and structural data.
  • Understanding NR2F6's structure is crucial for developing effective modulators.

Purpose of the Study:

  • To elucidate the structure of the unliganded NR2F6 ligand binding domain (LBD).
  • To identify molecular strategies for targeting NR2F6 activity.
  • To provide a basis for developing novel NR2F6 modulators for cancer therapy.

Main Methods:

  • Co-crystallization of the NR2F6 LBD with a peptide from the Nuclear Receptor Binding SET Domain Protein 1 (NSD1).
  • Structural elucidation of the unliganded NR2F6 LBD using X-ray crystallography.
  • Screening of covalent NR probes to identify NR2F6 inhibitors.

Main Results:

  • The crystal structure revealed an autorepressed, homodimeric conformation of the NR2F6 LBD with helix 12 blocking the canonical coregulator binding site.
  • An alternative binding surface for NSD1 was identified in the apo-NR2F6 structure.
  • Covalent NR probes targeting a specific cysteine residue were found to inhibit NR2F6 coregulator recruitment.

Conclusions:

  • The study provides the first structural insights into the ligand-independent activity of NR2F6.
  • The identified NR2F6 structure and binding interactions can guide the development of new cancer drugs.
  • These findings represent a significant step towards creating novel NR2F6 modulators for cancer immunotherapy.

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