8C5L

NR2F6 ligand binding domain in complex with NSD1 peptide

Summary for 8C5L

• Entry DOI: 10.2210/pdb8c5l/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Nuclear receptor subfamily 2 group F member 6, Histone-lysine N-methyltransferase, H3 lysine-36 specific, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: nr2f6, nsd1, nuclear receptor, ear-2, coregulator, transcription
• Biological source: Escherichia coli K-12; More
• Total number of polymer chains: 4
• Total formula weight: 129037.22

Authors

Oerlemans, G.J.M.,van den Oetelaar, M.C.M.,Brunsveld, L. (deposition date: 2023-01-09, release date: 2024-01-10, Last modification date: 2025-10-22)

Primary citation

Oerlemans, G.J.M.,van den Oetelaar, M.C.M.,van den Elzen, S.P.,Brunsveld, L.
Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6.
Acs Chem.Biol., 20:2308-2317, 2025

PubMed Abstract: The orphan nuclear receptor NR2F6 (Nuclear Receptor subfamily 2 group F member 6) is an emerging therapeutic target for cancer immunotherapy. Upregulation of NR2F6 expression in tumor cells has been linked to proliferation and metastasis, while in immune cells NR2F6 inhibits antitumor T-cell responses. Small molecule modulation of NR2F6 activity might therefore be a novel strategy in cancer treatment, benefiting from this dual role of NR2F6. However, there are no molecular strategies available for targeting NR2F6, hampered among others by lack of structural insights and appropriate biochemical assays. To overcome these challenges, several noncanonical nuclear receptor coregulator peptide motifs were identified to be constitutively recruited to the NR2F6 ligand binding domain (LBD). Co-crystallization of the NR2F6 LBD with a peptide from the coregulator Nuclear Receptor Binding SET Domain Protein 1 (NSD1) enabled, for the first time, the structural elucidation of the unliganded (apo) form of NR2F6. This revealed an autorepressed, homodimeric LBD conformation in which helix 12 folds over the canonical coregulator binding site, generating an alternative contact surface for NSD1 binding. Screening of a focused library of covalent NR probes identified compounds that preferentially target a cysteine residue near the NSD1 binding site, inhibiting NR2F6 coregulator recruitment. Combined, these results provide structural insights into the ligand-independent transcriptional activity of NR2F6 and may serve as a starting point for the development of novel NR2F6 modulators.

PubMed: 40931005
DOI: 10.1021/acschembio.5c00475

Experimental method

X-RAY DIFFRACTION (2.6 Å)