Classic Nuclear Receptor Ligands

1
Classic Nuclear Receptor Ligands
55a
Figure 1
2
Representative nuclear receptors, ligands and
disease targets
55b
Figure 2
3
Examples of medical uses of natural and synthetic
smallmolecules that act by regulating the
activities of nuclear receptors
56a

• Hormone replacement therapy
• Hypothyroidism (thyroid hormone)
• Gonadal failure (estrogens, progestins,
  androgens)
• Addisons disease (cortisol, prednisone,
  aldosterone)
• Ricketts/Osteomalacia (vitamin D)
• Inflammation (dexamethasone, prednisone)
• Malignancy
• Lymphoma, lymphocytic leukemia (dexamethasone)
• Acute promyelocytic leukemia (retinoic acid)
• Type 2 diabetes mellitus (thiazolidinediones)
• Hypertriglyceridemia (fibrates)

Figure 3
4
Examples of medical uses of synthetic modulators
56b

• Breast cancer (Selective estrogen receptor
  modulators SERMS)
• Prostate cancer (Androgen receptor antagonists)
• Hypertension/CHF (Mineralocorticoid receptor
  antagonists)

Figure 4
5
56c
Figure 5
6
56d
Figure 6
7
57a
Figure 7
8
Transcriptional activities of nuclear hormone
receptors
57b
Figure 8
9
Nuclear receptor domain structure
57c
Figure 9
10
Structure of the nuclear receptor DNA binding
domain
57d
Figure 10
11
Recognition of DNA by a glucocorticoid receptor
dimer
58a
Glucocorticoid response element
Figure 11
12
Mechanisms of HRE recognition by nuclear receptors
58b
Figure 12
13
Ligand-induced conformational changes in the RXR
LBD
58c
From Egea, et al., EMBO J 192592 2000
Figure 13
14
Ligand-induced exchange of co-activators for
co-repressors
58d
Figure 14
15
Examples of co-activator and co-repressor
complexes
59a
Figure 15
16
Structure of the nucleosome
59b
Figure 16
17
Related motifs in co-activators and co-repressors
mediate nuclear receptor interaction
59c
P160 nuclear receptorcoactivators
SRC-1 TIF2 P/CIP
Nuclear receptor interaction
CBP/p300 interaction
LXXLL
Nuclear receptorcorepressors
HDACinteraction
Nuclear receptor interaction
N-CoR SMRT
RD1
RD3
LXXIXXXL
Figure 17
18
Molecular mechanism mediating ligand-dependent
exchange of co-activators for co-repressors
59d
Figure 18
19
60a
Figure 19