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Structural insights into ligand-binding pocket formation in Nurr1 by molecular dynamics simulations

: Windshügel, B.


Journal of biomolecular structure & dynamics 37 (2019), No.17, pp.4651-4657
ISSN: 0739-1102
ISSN: 1538-0254
Journal Article
Fraunhofer IME ()

The nuclear receptor Nurr1 (NR4A2) has been identified as a potential target for the treatment of Parkinson's disease. In contrast to most other nuclear receptors, the X-ray crystal structure of the Nurr1 ligand-binding domain (LBD) lacks any ligand-binding pocket (LBP). However, NMR spectroscopy measurements have revealed that the known Nurr1 agonist docosahexaenoic acid (DHA) binds to a region within the LBD that corresponds to the classical NR ligand-binding pocket (LBP). In order to investigate the structural dynamics of the Nurr1 LBD and to study potential LBP formation, the conformational space of the receptor was sampled using a molecular dynamics (MD) simulation. Docking of DHA into 50,000 LBD structures extracted from the simulation revealed the existence of a transient LBP that is capable to fully harbor the compound. The location of the identified pocket overlaps with the ligand-binding site suggested by NMR experiments. Structural analysis of the protein-ligand complex showed that only modest structural rearrangements within the Nurr1 LBD are required for LBP formation. These findings may support structure-based drug discovery campaigns for the development of receptor-specific agonists.