1. NUCLEAR RECEPTOR
Presentation By : Vulli Aravind
Registration Number: PT/13
NIPER ,Hajipur
Department of Pharmacology &
Toxicology
2. Nuclear receptors (NRs) are a major transcription factor family whose
members selectively bind small-molecule lipophilic ligands and
transduce those signals into specific changes in gene programs.
The nuclear receptor proteins are transcription factors able to regulate
the expression of genes controlling numerous physiological processes,
such as reproduction, development, and metabolism.
Nuclear receptors are located in the cytosol and migrate to the nuclear
compartment when a ligand is present.
NUCLEAR RECEPTOR
3. STRUCTURE OF NUCLEAR RECEPTOR
Nuclear hormone receptors contain six major domains in a single
polypeptide chain.
• [A-B] N-regulatory domain
• [C] DNA binding domain
• [D] Hinge region
• [E] Ligand binding domain
• [F] C-terminal domain
4. The N-terminal domain can contain an activation region
(AF-1) essential for transcriptional regulation.
The core domain of the receptor is highly conserved region with
two zinc fingers that bind to DNA
(the DNA-binding domain).
The N-terminal activation region (AF-1) is subject to regulation
by phosphorylation and other mechanisms that stimulate or inhibit
transcription.
The C-terminal half of the molecule contains a hinge region
(which can be involved in binding DNA), the domain responsible for
binding the hormone or ligand (the LBD), and specific sets of amino
acid residues for binding co-activators and co-repressors in a second
activation region (AF-2).
5. The LBD is formed from a bundle of 12 helices,ligand binding
induces a major conformational change in helix 12 that affects the
binding of the co-regulatory proteins essential for activation of
receptor-DNA complex.
When binding to DNA, most of the nuclear hormone receptors act
as dimers some as homodimers, others as heterodimers.
Steroid hormone receptors such as the glucocorticoid receptor are
commonly homodimers whereas those for lipids are heterodimers
with the RXR receptor. ligand but also on the ratio of co-activators
and co-repressors recruited to the complex.
The activity of the nuclear hormone receptors in a given cell
depends not only on the ligand but also on the ratio of co-activators
and co-repressors recruited to the complex.
6. Co-activators recruit enzymes to the transcription complex that
modify chromatin, such as histone acetylase that serves to unravel
DNA for transcription.
Co-repressors recruit proteins such as histone deacetylase, which
keeps DNA tightly packed and inhibits transcription.
7. CLASSIFICATION OF NUCLEAR RECEPTORS
CLASS OF
NUCLEAR
RECEPTOR
I II III
LOCATION Cytoplasm Nucleus Endocrine
FORMS Homodimer Heterodimer RXR
Heterodimer
EXAMPLES GR,MR,ER PPAR,RXR,FXR TR,VDR
8. CLASS II NUCLEAR RECEPTOR
The Ligands are generally lipids already present to some extent within
the cell located on the nucleus.
Its mechanism of action shows that it directly binds to DNA
fragments.
These NRs almost always operate as heterodimers together with
retinoid receptor (RXR).
These heterodimers are bound to their response element regardless of
whether ligands are present and in the absence of heat shock proteins.
This class includes the peroxisome proliferator –activated receptor
(PPAR) that recognises fatty acids , the liver oxysterol receptor (LXR)
that recognises and acts as a cholesterol sensor.
9. These are a group of nuclear receptor proteins that function as
transcription factors regulating the expression of genes.
These are ligand-activated transcription factors belonging to the
nuclear receptor family.
PPARs play essential roles in the regulation of cellular
differentiation, development, and metabolism (carbohydrate, lipid,
protein).
Upon activation it binds as a heterodimer with retinoid
X receptor (RXR) to peroxisome response elements in genes
involved in fatty acid oxidation.
These nuclear hormone receptor superfamily comprising of the
following three subtypes: PPARα, PPAR γ and PPARβ/δ
PPARs [peroxisome proliferator-activated receptors]
10. MODE OF ACTION OF PPARγ
PPARγ and RXR form a heterodimer, which is activated by the respective
ligands.
The activated PPARγ/RXR heterodimer will be translocated into nucleus and
regulates downstream target genes in concert with nuclear receptor co-
activators.
12. Glitazone’s
CONSIDERING ‘GLITAZONES ‘ AS A PPARγ AGONIST THE MOA AS FOLLOWS;
Selective agonists of PPARγ binds to the
receptor
Activate insulin responsive genes-regulate
carbohydrate & lipid metabolism
Inhibits hepatic
gluconeogenesis
Promotes
Lipogenesis
Sensitizes the peripheral tissues to insulin
Increase
glucose
transport
Decreased
Blood
Glucose
13. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics
https://www.researchgate.net/figure/Metabolic-regulation-
of-PPARg-as-a-nuclear-receptor-PPAR-
Peroxisome_fig1_321483816/amp
https://www.researchgate.net/figure/Osteosarcoma-OS-
development-and-nuclear-receptor-agonist-mediated-
differentiation_fig2_41562757
