Nuclear Receptor - Structure

Structure

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.
  • 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.
  • 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.

DNA binding domain (DBD)

Crystallographic 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.
Identifiers
Symbol zf-C4
Pfam PF00105
InterPro IPR001628
SMART SM00399
PROSITE PDOC00031
SCOP 1hra
SUPERFAMILY 1hra
CDD cd06916
Available protein structures:
Pfam structures
PDB RCSB PDB; PDBe
PDBsum structure summary
Ligand-binding domain (LBD)

Crystallographic structure of the ligand binding domain of the human RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta).
Identifiers
Symbol Hormone_recep
Pfam PF00104
InterPro IPR000536
SMART SM00430
SCOP 1lbd
SUPERFAMILY 1lbd
CDD cd06157
Available protein structures:
Pfam structures
PDB RCSB PDB; PDBe
PDBsum structure summary


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