Structural basis of NR4A1 bound to the human pituitary proopiomelanocortin gene promoter.

The nuclear receptor NR4A subfamily (NR4A1/NGFI-B, NR4A2/Nurr1 and NR4A3/NOR-1) can recognize different classes of DNA response elements either as a monomer, homodimer, or heterodimer. In this study, we determined the structure of the NR4A1 DNA-binding domain (NR4A1-DBD) bound to natural Nur-responsive elements (NurREs) in the promoter region of the pituitary proopiomelanocortin (POMC) gene (NurRE_POMC) at 3.12 Å resolution. The NR4A1-DBD molecules bound independently to this element in our structure. The N-terminal helix H1 forms specific contacts with major groove, and C-terminal extension interact extensively with minor groove. Moreover our modelling structure of NR4A1 large fragment complexed with NurRE_POMC indicated that ligand binding domain of NR4A might form dimer interactions to help recognize DNA. Overall, our analyses provide a molecular basis for DNA binding of NR4A proteins as a homodimer and novel insight into the molecular functions of NR4A modulation of gene expression.

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