Fig. 1: Structure and function of NR1 receptors.
a Phylogenetic tree of the NR family comprising 48 members in humans. NR1 family in red. b The archetypal domain structure of NRs is composed of an unordered N-terminal domain (NTD), containing the ligand-independent activation function 1 (AF-1), a DNA binding domain (DBD) comprising two zinc finger motifs, a flexible hinge region, and a ligand binding domain (LBD) with the ligand-dependent activation function AF-2. c Molecular mechanism of NR activity. The example shows the full-length PPARγ-RXRα heterodimer (pdb id: 3dzy68, colors corresponding to modular domain structure in (b)) bound to DNA (gray). In their inactive conformation, in the absence of a ligand, NRs bind co-repressors (dark purple), resulting in repression of gene expression. Agonist binding (blue) induces the active conformation, leading to co-repressor displacement and co-activator (cyan, pdb id: 2fvj69 for co-activator placement) recruitment to activate gene expression. d NR modulation by different types of ligands involves different conformational changes in the NR LBD affecting the position of the AF-2 (red): agonists stabilize an active conformation with AF-2 bound to the LBD core (PPARγ with bound agonist rosiglitazone; pdb id: 7awc70); partial agonists cause weaker stabilization with potentially shifted AF-2 (PPARγ with bound partial agonist AL26-29; pdb id: 5hzc71); antagonists prevent agonist binding and do not stabilize the active conformation (PPARγ with bound antagonist SR11023; pdb id: 6c5t72); inverse agonists block the constitutive activity of NRs like RORs by stabilizing the inactive state (RORγ with bound inverse agonist; pdb id: 6slz). Structural and molecular mechanisms of NR modulation have been reviewed in7,73,74. e Some NRs like NR1D act primarily as transcriptional repressors and recruit co-repressors (revERBα with agonist and co-repressor NCoR1 in purple; pdb id: 8d8i75).
