BIOLOGY 1 Nuclear Receptors Flashcards
Where are nuclear receptors found
Cytoplasm - can enter nucleus to regulate genes
What is the relatinship between Kd of the ligand to the nuclear receptor
Inverse
Structure of nuclear receptor
Two key binding regions
DNA binding domain & ligand binding domain
Examples of nuclear receptor ligands
Cholesterol
Estrogens
Cortisol
Aldosterone
Bile acids
Bit D3
Glucocorticoids
What are DNA binding domains contain
Tetrahedral zinc - binds to 4 cystines
What do DNA binding domains bind to
Recognise a 6 base pair repeat - hormone response element
Found in regulatory regions of NR targets
What influences specificity for NR complexes in the DBD
Orientation and spacing of half sites (consensus sequence - variations exist)
Can be in opposite or same direction and have a certain number of spaces between them
Describe the structure of a ligand binding domain
LBDs contain a ligand binding pocket
They have a preference for a specific ligand
Ligand binding leads to a conformational change
What happens when a ligand binds to the ligand binding domain
Conformational change
Alters position of activator helix
Exposes cofactor binding site on lbd
What is a heterogenous disease
Occurs in different cell types
Ie basal type, medullary, ducal, lobular, mucinous
How are breast cancers classifies (4)
Tumour size and morphology
Genetic markers: BRCA1+2 mutations
Gene transcription factors
Breast cancer treatments (5)
Surgery
Radiotherapy
Chemotherapy
Hormone therapy
Targeted therapies
What drugs are used in hormone therapy for breast cancer
Tamoxifen (antoestrogen)
Aromatise inhibitors (arimidex, aromasin, femara)
How does tamoxifen work
Block estrogen dependant growth by mimicking estradiol and binding to the ER (estrogen receptor) LBD
This pushes the activation helix out so it can’t form a complex
What are some of the off- target side effects of tamoxifen
- partial agonists in bone = helps to prevent osteoporosis over time
- partial agonist in endometrium = inc risk of cervical cancer over time
