L4: Receptor Superfamilies Flashcards
What are the possible drug targets?
- Receptors,
- ion channels,
- enzymes,
- transporters
What are the possible Ligand-Receptor interactions?
1) Ligand binds to cell surface receptors (rapid)
water soluble molecules, short half-life, which modulate:
- cAMP, phosphtidylinositides
- excitability
- a kinase/phosphatase cascade
2) Ligand binds to intracellular receptors (slow)
lipophilic molecules that diffuse through the plasma membrane, e.g. steroid and thyroid hormones
Name receptor superfamilies
- ionotropic (ligand gated ion channels)
- metabotropic (G-protein coupled receptors)
- kinase linked receptors
- nuclear / intracellular receptors
Describe ionotropic (ligand gated ion channels) receptors (activation speed, position within the membrane, example)
- very quick, millisecond activation
- membrane spanning
- hyperpolarization (less likely to activate) / depolarization (activates quicker)
- e.g. nicotinic AChR
What’s the speed of ionotropic receptors activation?
very quick, millisecond
Describe metabotropic (GPCRs) receptors (activation speed, position within the membrane, function, example)
- quick, but not as ionotropic, activation in seconds
- membrane spanning
- second messengers / protein phosphorylation
- e.g. muscarinic AChR
What’s the speed of metabotropic receptors activation?
quick, but not as ionotropic, activation in seconds
Describe kinase linked receptors (activation speed, position within the membrane, mechanism, example)
- slow, activation in hours
- membrane spanning
- protein phosphorylation => changes in gene transcription and protein synthesis
- e.g. insulin, cytokines
What’s the speed of kinase-linked receptors activation?
Slow, activation in hours
Describe nuclear / intracellular receptors (solubility, activation speed, position, mechanism, example)
- intracellular, ligand must pass through cell membrane (must be lipophilic)
- transduction of effect takes hours
- ligand-receptor => DNA => changes in gene transcription and protein synthesis
- e.g. steroid hormones, vitamin D
What’s the speed of nuclear / intracellular receptors activation?
Transduction of effect takes hours
What are the possible ligands of nuclear / intracellular receptors?
- steroid hormones (oestrogen (oestrogen receptor); testosterone (androgen receptor); cortisol (glucocorticoid receptor); aldosterone (mineralcorticoid receptor); progesterone (progesterone receptor))
- thyroid hormone
- vitamin D
What is the structure of nuclear receptors?
- regulatory domain (Activation Function-1; regulates R activity)
- DNA binding domain
- Hinge (shape of receptor)
- ligand binding domain (Activation Function-2)
Describe regulatory domain of nuclear receptors (variability, structure, function)
- very variable, both sequence and length
- contains transcriptional activation function, AF-1
- AF-1 binds elements (co-activator or co-repressor proteins) that modify the ability of the receptor to increase or decrease gene transcription via DNA binding domain
How variable or conserved is regulatory domain of nuclear receptors?
Very variable, both sequence and length
Describe DNA binding domain of nuclear receptors (variability, action, structure)
- highly conserved
- localises receptor on DNA and involved in receptor dimerisation
- contains 2 Zn2+ fingers that wrap around the DNA helix
- 4 cysteines in each finger chelate one Zn2+ ion
- proximal zinc finger (P box; determines specificity) and distal (D box)
How variable or conserved is DNA binding domain of nuclear receptors?
highly conserved
What’s the mechanism of action of DNA binding domain of nuclear receptors?
localises receptor on DNA and involved in receptor dimerisation
What’s the structure of DNA binding domain of nuclear receptors?
- contains 2 Zn2+ fingers that wrap around the DNA helix
- 4 cysteines in each finger chelate one Zn2+ ion
- proximal zinc finger (P box; determines specificity) and distal (D box)
What are response elements in nuclear receptors context?
- Nuclear receptors regulate transcription by binding to DNA-response elements using their conserved DNA-binding domains.
- These response elements contain conserved hexameric sequences that can be arranged in various bipartite configurations, including inverted and direct repeats.
- Response elements show palindrome sequences.
Describe hinge domain of nuclear receptors
- less well conserved
- flexible, links the ligand-binding domain to the DNA binding domain - allows tertiary structure of protein
- role in nuclear localisation
How variable or conserved is hinge domain of nuclear receptors?
less well conserved
What is the role of hinge domain of nuclear receptors?
- flexible, links the ligand-binding domain to the DNA binding domain - allows tertiary structure of protein
- role in nuclear localisation
Describe ligand binding domain of nuclear receptors (variability, function, role)
- variable sequence
- involved in nuclear localisation and dimerisation
- important role in regulation of ligand dependent transcriptional activation through AF-2 sequence in carboxy terminus
- agonist ligands stabilise the receptor conformation that is optimal for efficient interaction with co-activators, with AF-2 domain exposed
- antagonists have bulky side chains that hinder H12 from aligning in the agonist conformation.
