Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

Ian Mitchelle S. de Vera, Paola Munoz-Tello, Jie Zheng, Venkatasubramanian Dharmarajan, David P. Marciano, Edna Matta-Camacho, Pankaj Kumar Giri, Jinsai Shang, Travis S. Hughes, Mark Rance, Patrick R. Griffin, Douglas J. Kojetin

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.

Original languageEnglish
Pages (from-to)66-77.e5
Issue number1
StatePublished - Jan 2 2019


  • NMR spectroscopy
  • NR4A2
  • Nurr1
  • dynamic pocket
  • hydrogen deuterium exchange mass spectrometry
  • ligand binding
  • molecular dynamics simulations
  • orphan nuclear receptor
  • unsaturated fatty acids


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