Drug Targets: Nuclear Receptors Flashcards
Nuclear receptors found where?
In the cytoplasm
Anything that binds to nuclear receptor must be lipid soluble. Why?
It has to cross the membrane and get into the cytoplasm before it can interact with the receptor
Role of n-terminal variable domain
Regulate transcriptional activity
Role of dna-binding domain (DBD)
Highly conserved; binds receptor to hormone response element in DNA by two zinc-containing regions
Role of hinge region
Enables intracellular translocation to the nucleus
Role of ligand-binding domain(LBD)
Moderately conserved; enables specific ligand binding; contains nuclear localisation sequence (NLS); also binds chaperone proteins and facilitates receptor dimerisation
AF1 role
Can promote the binding of other cofactors to the genetic material to influence the effects of the ligand receptor complex
AF2 role
May/may not be present
-Similar to AF1 - serves to promote binding of activating factors
Endogenous ligand
A naturally occurring small molecule that elicits a conformational change in the nuclear receptor upon binding
4 classes of nuclear receptors
2 major classes and 2 minor classes
Without hinge region what happens?
No translocation = no receptor action
Hinge region promotes dimerisation of nuclear receptors
What type of ligand binding are type 1 receptors? Location?
Homodimers
Location -cytosolic
What type of ligand binding are type 2 receptors? Location?
Heterodimers often with RXR
Location- nuclear
Endogenous ligand for oestrogen receptor?
Sex hormone oestrogen
Mechanism of action for oestrogen
- Bind to its receptor (oestrogen) in the cytoplasm
- in cytoplasm you get dimerisation and couple of activation factors
- receptor and ligand complex move to the nucleus where it will bind to destrogen response element on the DNA
- activation factors stimulate the action of the co-activators= form linkage of receptor with RNA polymerase (role-regulate transcription of genetic material)
- get significant effects upon cellular function
Overactivity of the oestrogen receptor in breast tissue can lead to?
example of drug treatment
Forms of breast cancer
Drug-tamoxifen, fulvestrant
Tamoxifen leads to? Fully activated transcription or partially activated transcription or no transcription
Partially activated transcription
Fulvestrant leads to? Fully activated transcription or partially activated transcription or no transcription
No transcription
Oestradiol leads to? Fully activated transcription or partially activated transcription or no transcription
Fully activated transcription
Mechanism of action for tamoxifen
- Binds to oestrogen receptor and will act to modulate the function of the receptor (still get dimerisation and translocation in nucleus)
-Activation factor = only one activation factor, before had couple of coactivators (AF1 active, AF2 inactive)
-Results in partially activated transcription
Why is tamoxifen described as a partial antagonist?
Results in partially activated transcription as there is only one activation factor recruiting activators involved
Mechanism of action for fulvestrant
-Accelerated receptor degradation as a consequence of binding
- inactivation AF1 and 2 leads to reduced nuclear localisation of the inactive oestrogen receptor
Still get nuclear translocation but no activation factors involved = no transcription
Synthetic glucocorticoids can be used as?
Anti-inflammatory and immunosuppressive compounds
Prednisolone is what type of glucocorticoid ?
Synthetic, anti-inflammatory and immunosuppressant effects
Nuclear factor kappa B
Receptor believed to be important in inflammatory signaling
Mechanism of action for prednisolone
- With help of a glucose response element, it bind to DNA
-Once it binds to its receptor, responsible for inhibiting another receptor, nuclear factor kappa B
-Moves into the nucleus and the effect of the glucocorticoid is to inhibit the function of the receptor
Vamorolone is currently in trials for?
Muscular dystrophy where anti-inflammatory component is more important than immunosuppressive effect
Pioglitazone is used in treatment for?
Diabetes
pioglitazone : is receptor has number of different effect such as?
- Effect in cytoplasm interfering with second messenger systems
- also translocations in the nucleus where it car be heterodimerised with retinoid receptor
Mechanism of action for pioglitazone
Binds to peroxisome proliferator activated receptor y (PPARy)
Alters transcription of genes influencing carbohydrate and lipid metabolism
-Activation of PPARy increases transcription of insulin - responsive genes
Finerenore in clinical trials for?
Kidney disease and heart failure
Aldosterone is important in terms of?
Regulation of water balance and in pathological conditions, the hormone aldosterone via activation of mineralocorticoid receptors (MR), can result in fibrosis (thickening/scarring of tissue)
Role of finerenone
To try and reduce the effects of aldosterone by blocking it with finerenone , reducing the incidence of fibrosis
Rosiglitazone: despite being approved by regulators, there is issues regarding?
Its cardiovascular safety
