Textures of Ligand Binding Flashcards
Why are receptor-ligand interactions important? (3)
- Receptors mediate action of natural ligands as well as most drugs
- Receptors determine quantitative relationship between concentration of ligand and pharmacologic effect
- Receptors are responsible for selectivity of drug action
Receptor affinity for a ligand determines the _____________ of the ligand needed
concentration
What limits the maximal effect of a drug?
Number of receptors
What determines whether and with which affinity a ligand binds to a specific receptor?
Molecular shape, size and charge of a ligand
What can alter therapeutic/toxic effects of ligand-receptor binding? Why?
changes in ligand chemical structure because this changes affinity for it’s receptor
Some ligands are intrinsic to it’s receptor, what does this mean?
The segment is on the receptor sequence and needs to be cleaved to reveal it.
How does a hormone get to it’s receptor? Where does it come from?
It comes from other cells and needs to travel a certain distance from the bloodstream before reaching target tissue/cell
Some ligands are already close to their receptor, ehat does it take for them to become active and bind to the receptor?
An external trigger such as light, which alters it’s configuration
What maintains a protein’s tertiary structure in Class C GPCRs? Which domain assures this?
Disulfide bonds maintain the structure. Sushi domains create these bonds.
What can affect ligand binding capacities?
Diversity among extracellular domains
Why do different ligands, acting on the same receptor, cause different changes in receptor conformation and different signals?
Because their structure is different and they bind different sites of the receptor
What is the key to activate the receptor? How does this happen?
Disruption of the ionic clock in transmembrane.
Amino acids binded together are disrupted and the receptor is broken in order to be activated (induced by conformational change)
What causes activation of the rhodopsin receptor? This causes what?
Light
Causes a change in retinal conformation
What holds the transmembrane regions of the Rhodopsin receptor in an inactive conformation?
11-cis retinal
Why are there so many possibilities of ligand-receptor binding?
Receptors can bind to different things (other receptor, G protein, hormone, etc…)
It can also dimerize which is basically two receptors (ligand could bind to one dimer, but not the other, vice-versa, this changes the signal)
Why does the dimerization of a receptor increase the different types of signals?
Ligand could bind to one dimer, but not the other, or vice-versa, or both could be binded to a ligand, or neither. This gives many different signals
Competitive antagonist (4)
Binds to same receptor site as agonist
Inhibition can be overcome by increasing agonist concentration (Reversible)
Affects potency
Clinically useful
Non-competitive antagonist (4)
Binds covalently to same site as agonist (irreversible) or to a site distinct from that of agonist
Inhibition not overcome by increasing agonist concentration
Affects afficacy
Limited clinical use
Inverse agonist stabilizes __________ form of receptor
inactive
What is the technical issue with inverse agonists?
These ligands are identified using active receptors because to see a decreased response, you need to see an elevated/active response first
What is protean agonism
Ligand behaves as agonist and antagonist at the same receptor depending on effector pathway
Two different synonyms of protean agonism
Biased agonism
Functional selectivity
Protean agonism :
How do you efficiently test the behavior of a ligand?
We must study different signaling pathways
Proxyfan at Histamine H3 receptor:
When is proxyfan a partial agonist on the recombinant receptor?
MAPK activity
GTP-gamma binding
Inhibition of cAMP formation
Proxyfan at Histamine H3 receptor:
When is proxyfan a neutral antagonist on the recombinant receptor?
AA release (300)
Proxyfan at Histamine H3 receptor:
When is proxyfan a partial inverse agonist on the recombinant receptor?
AA release (1000)
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying histamine release in RAT brain?
Partial agonist at 20 mM K+
Neutral antagonist at 55 mM K+
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying histamine release in MOUSE brain?
Neutral antagonist at 20 mM K+ and 55 mM K+
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying GTP-gamma binding in rodent brain?
neutral antagonist
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying t-MeHA level in mouse and rat brain?
Mouse : neutral antagonist
Rat : partial inverse agonist
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying Cyclophosphamide-induced cystitis in mouse?
Full agonist
Proxyfan at Histamine H3 receptor:
NATIVE receptor : what is proxyfan when studying Sleep-wake cycle in mouse and cat?
Mouse : full inverse agonist
Cat : Full agonist
Orthosteric binding site
Primary binding site recognized by endogenous agonist or hormone
Allosteric binding site
Any binding site on a receptor protein that can modulate binding properties of the orthosteric site by conformation change of receptor
Allosteric modulators are controlled by the amount of __________________ : what is this effect called?
orthosteric ligands binded, requires presence of endogenous agonists
Ceiling effect
Allosteric modulators affect what? (2)
Efficacy
Binding of ligand
Allosteric protomers?
Receptor dimers where one receptor accepts allosteric ligands which modulates orthosteric ligand on other receptor
Collateral efficacy vs linear efficacy?
Collateral : selective not all-inclusive behaviours resulting from the binding of some ligands
Linear : all behaviours emanating from a single receptor
