Structural and mechanistic profiling of Nurr1 modulation by vidofludimus enables structure-guided ligand design

The neuroprotective transcription factor nuclear receptor related 1 (Nurr1, NR4A2) is in the focus of biomedical research for its promising neuroprotective role in Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Its activity can be controlled by ligands offering access to pharmacological Nurr1 modulation. However, the binding epitope(s) and molecular activation mechanisms of synthetic Nurr1 activators remained elusive but are essential to advance Nurr1 ligands towards new medicines. Here we characterized Nurr1 dimer dissociation and coregulator release as molecular contributions to Nurr1 activation by vidofludimus and locate its binding in an allosteric surface pocket lined by helices 1, 5, 7, and 8 by mutagenesis and molecular dynamics simulation. Structure-guided ligand design using these insights resulted in an optimized Nurr1 agonist with substantially enhanced potency and binding affinity. Our results provide a structural and molecular basis for Nurr1 activation by a synthetic agonist which was lacking for rational ligand design.