page_title: Nuclear receptor
section_title: Structure
hierarchical_section_title: Nuclear receptor / Structure
caption_attribution_description: English: Structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double strained DNA (magenta). Zinc atoms of are depicted as grey spheres.[1]
context_page_description: In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
  Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors generally only happens when a ligand — a molecule that affects the receptor's behavior — is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up- or down-regulation of gene expression.
  A unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis.
context_section_description: Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons.
  Nuclear receptors are modular in structure and contain the following domains:
  (A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand.  The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain (see below) to produce a more robust upregulation of gene expression.  The A-B domain is highly variable in sequence between various nuclear receptors.
  (C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers that binds to specific sequences of DNA called hormone response elements (HRE).
  (D) Hinge region: Thought to be a flexible domain that connects the DBD with the LBD.  Influences intracellular trafficking and subcellular distribution with a target peptide sequence.
  (E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors.  The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread").  The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling".  Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins.  The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand, controlled by the conformation of helix 12 (H12).
  (F) C-terminal domain: Highly variable in sequence between various nuclear receptors.
  The N-terminal (A/B), DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp),  one binding on DR4 (by 4 bp).
caption: Crystallographic structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double stranded DNA (magenta).  Zinc atoms of are depicted as grey spheres.[24]
exif: {}