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NR3C1
NR3C1 Full Name
nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
NR3C1 Introduction
Nuclear Receptor Subfamily 3, Group C, Member 1 (NR3C1) encodes the glucocorticoid receptor (GR) protein. GR is expressed in almost all human tissues and cells, which underpins the systemic effects of glucocorticoids. However, its expression levels are precisely regulated across different tissues, developmental stages, and physiological or pathological conditions. This spatiotemporal specificity in expression is essential for the precision of its functions. Similar to other nuclear receptors, the GR protein encoded by NR3C1 has a typical modular structure composed of three core functional domains, each with distinct roles that work together to complete the entire process from signal reception to gene expression regulation.
Figure 1. Schematic representation of the protein isoforms expressed by both alleles of MR (NR3C2) and GR (NR3C1) genes in the patient. (Source: Morales M, et al. 2022)
N-terminal Domain (NTD), also known as Region A/B, is the longest and most variable region of the GR protein. It contains an important transcriptional activation function domain 1 (AF-1), which possesses ligand-independent transcriptional activation capability. The NTD itself is an intrinsically disordered region (IDR). This structural flexibility allows it to act as a "molecular scaffold," recruiting a large number of co-activators or co-repressors to finely regulate transcription. Post-translational modifications such as phosphorylation of the NTD are important mechanisms for modulating GR activity, with different modification patterns determining whether GR activates or represses specific target genes. DNA-Binding Domain (DBD), also known as Region C, is the most structurally conserved region of the GR protein and serves as its identity marker as a transcription factor. The DBD consists of approximately 70 amino acids and its core structure features two zinc-finger motifs. Each zinc finger is formed by a zinc ion coordinated with four cysteine residues, creating a highly stable structure crucial for GR to recognize and bind to specific DNA sequences known as glucocorticoid response elements (GREs) located in the promoter or enhancer regions of target genes. A typical GRE is a palindromic sequence, and GR usually binds to it as a homodimer to initiate or repress gene transcription. The DBD is not only responsible for precise DNA recognition but also participates in GR dimerization and interactions with other transcription factors.
Ligand-Binding Domain (LBD), also known as Region E, is located at the C-terminus of the protein and serves as the specific binding site for glucocorticoids (such as cortisol). The LBD is composed of 12 α-helices and one β-sheet, forming a compact hydrophobic "pocket." The precise three-dimensional conformation of this pocket determines its selectivity and affinity for ligands. Ligand binding, akin to a key turning in a lock, induces significant conformational changes in the LBD. This change triggers a series of cascading events: first, the dissociation of associated molecular chaperone protein complexes (such as Hsp90); second, the promotion of GR dimerization; and finally, the formation of a surface capable of recruiting co-activators, known as the activation function 2 (AF-2) domain. Thus, the LBD functions not only as a signal receiver but also as a "molecular switch" that transmits the signal downstream.
Alternate Names for NR3C1
NR3C1; nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor); GR; GCR; GRL; GCCR; GCRST; glucocorticoid receptor; glucocorticoid nuclear receptor variant 1;
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