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Nuclear receptors (also known as nuclear hormone receptors) are a large family of transcription factors that bind directly to DNA to regulate the expression of target genes. They regulate the cellular response to hormones such as sex steroids, vitamin D3, adrenal steroids and other metabolic ligands, and are involved in metabolism, development and reproduction.
The nuclear receptor superfamily is classified by sequence alignment and phylogenetic tree construction into six main subfamilies:
●Thyroid Hormone Receptor-like: Includes thyroid receptor, retinoic acid receptor, PPAR, LXR, FXR, VDR, PXR and CAR
●Retinoid X Receptor-like: Includes RXR
●Estrogen Receptor-like (also known as steroid hormone receptors): Includes receptors for estrogen (ER), androgen, glucocorticoid, mineralocorticoid and progesterone
●Nerve Growth Factor IB-like
●Steroidogenic Factor-like
●Germ Cell Nuclear Factor-like
Overview of Receptor Types
|
Enzyme-Linked Receptors |
G-Protein-Coupled Receptors |
Ligand-Gated Ion Channels |
Intracellular Receptors |
|
|
Location |
Cell membrane |
Cell membrane |
Cell membrane |
Cytoplasm or nucleus |
|
Effector |
Protein kinases |
Channel or enzyme |
Ion channel |
Gene transcription |
|
Coupling |
Direct |
G-protein |
Direct |
Via DNA |
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Structure |
Single transmembrane helix linking extracellular receptor domain to intracellular enzyme (often kinases) domain. Hormones bind to a receptor dimer to result in activation. |
7 trans-membrane helices with intracellular G-protein-coupling domain |
Oligomeric assembly of 4-5 subunits surrounding a central pore |
Monomeric structure with separate receptor and DNA-binding domains |
|
Examples |
Insulin, growth factors, cytokine receptors |
Muscarinic acetylcholine receptors, adrenoceptors |
Nicotinic acetylcholine receptors, GABAA receptor |
Estrogen receptors, vitamin A receptors |
Structural Insight into Nuclear Receptor Action
X-ray crystal structures of nuclear receptors, both full-length and discrete domains, have provided critical information on how ligands and DNA response elements are recognized, how they dimerize, and interact with co-regulators.
Overall architecture
Despite diversity in the size, shape, and charges of activating ligands, almost all members of the nuclear receptor superfamily share a common modular domain structure. Except for the atypical receptors SHP and DAX, the overall architecture is composed of five domains: A–E. Each of these subdomains plays a specific role in receptor biology. The mass of NRs can vary but they are generally between 66 and 100 kD.
A/B: N-terminal domain (NTD): The NTD is a highly disordered domain, which explains why the NTD is not amenable to structural analysis. Additionally, there is little sequence conservation between NR NTDs and there is a large disparity in the size of this domain.
The NTD contains the activator Function-1 region (AF-1), which interacts with a variety of co-regulator proteins in a cell- and promoter-specific manner. For all NRs, the majority of the domain is disordered. However, the GR NTD can adopt a more alpha-helical structure when co-regulators are bound. This region also gives rise to multiple isoforms through alternative splicing, as seen in TR and GR. Finally, the NTD is the target for numerous post-translational modifications including phosphorylation, SUMOylation, and acetylation. These modifications have varying effects, both driving and repressing transcription.
C: DNA binding domain (DBD): This region is the most conserved among all nuclear receptor domains.The DBD has two subdomains that each contains four cysteine residues that co-ordinate a zinc ion to create the canonical DNA-binding zinc finger motif. Each zinc finger is then followed by an amphipathic helix and a peptide loop.The first subdomain contains the DNA-reading helix, which interacts with the major groove to make base-specific interactions with the DNA. The second subdomain helix makes non-specific contacts with the DNA backbone. The peptide loop in this subdomain contains the distal box, or “D box,” that contains residues for receptor dimerization.Some NRs, like LRH-1 and GCNF, contain a DBD C-terminal extension (CTE) that makes additional base-specific contacts within the DNA minor groove.
D: Hinge Region: The hinge region is a short, flexible linker between the DBD and the LBD. This region has the least sequence and size conservation between nuclear receptors. Like the NTD, this region is also a site for regulatory PTMs. The hinge can also contain a nuclear localization signal.
E: Ligand binding domain (LBD): The LBD is a complex allosteric signaling domain that not only binds to ligands but also interacts directly with co-regulator proteins. This structurally conserved domain commonly contains 11 α-helices and four β-strands that fold into three parallel layers to form an alpha helical sandwich. This folding creates a hydrophobic ligand-binding pocket (LBP) at the base of the receptor. Superposition of NR LBD structures reveals that the top part of the receptor is most similar whereas the base, which contains the LBP, is more variable. This variability across NRs at the ligand-binding region allows NRs to recognize a diverse cadre of ligands.
The LBD contains another activation function surface (AF-2), which is composed of helices 3, 4, and 12. Helix 12, or the activation function helix (AF-H) has been shown to be conformationally dynamic upon ligand binding, altering the orientation of AF-2 to facilitate interaction with different co-regulator proteins.
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