Advances in our structural understanding of orphan nuclear receptors

•More than half of human nuclear receptors (NRs) lack characterized natural ligands.•Structural characterization has led to the discovery of unexpected ligands.•Structural studies increased our understanding of NR selectivity and specificity.•Many NRs are ligand independent, questioning canonical regulatory mechanisms.•Understanding interdomain communication is a challenging but advancing area.

Nuclear receptors (NRs) are key players in the regulation of gene expression, coordinating protein assemblies upon their surfaces. NRs are regulated by ligand binding, which remodels the interaction surfaces and subsequently influences macromolecular complex formation. Structural biology has been instrumental in the discovery of some of these ligands, but there are still orphan NRs (ONRs) whose bona fide ligands have yet to be identified. Over the past decade, fundamental structural and functional breakthroughs have led to a deeper understanding of ONR actions and their multidomain organization. Here, we summarize the structural advances in ONRs with implications for the therapeutic treatment of diseases such as metabolic syndrome and cancer.