GMS6504 Exam 2, GMS 6504, GMS 6504 1, GMS 6504 REVIEW EXAM 1 All
Questions And Accurate Answers Combined 2024-2025
We can now easily express any gene anywhere
Opens up many possibilities
We can titrate in receptors
Fine-tune sensitivity
Allosteric Modulation
Antagonist binds to a different site than the agonist
Causes conformational change
Reduced Side Effects
Orthosteric antagonists bind at the agonist binding site
Many endogenous receptors for each endogenous ligand
Can potentiate natural responses
Control of Conformation
Receptors constantly change shape
Allosteric modulator acts like doorstop to keep one particular conformation
Effects of Modulation
May increase or decrease agonist affinity
Separate effects on potency and efficacy
Classes of Allosteric Modulators
Defined in terms of effects on a (affinity) and B (efficacy)
NAM
NAM-agonist
PAM
PAM-agonist
,PAM-antagonist
Negative Allosteric Modulator (NAM)
a and/or B <1
NAM-agonist
NAM that also produces some response on its own
Postive Allosteric Modulator (PAM)
a and/or B >1
PAM-agonist
PAM with efficacy of their own (partial agonist)
PAM-antagonist
a >1, B <1
Studying Allosteric Modulators
Modulators have no inherent activity; only terms of effects on agonist binding
IC50 of an allostetric modulator depends not only on the affinity of the modulator but also
the affinity, efficacy, and concentration of the agonist Orthosteric Antagonist binds to
same location as agonist Orthosteric vs Allosteric Orthosteric= one or the other
Allosteric= bind at different locations but both can bind Saturable add enough antagonist
eventually get to point where adding no more antagonist causes extra antagonism
Surmountable add enough agonist can overcome antagonist property of competitive
antagonist limit to inhibition
insaturable, surmountable antagonist
100% response at different concentrations, wide x-axis
Saturable, surmountable antagonist
100% response at different concentrations, thin x-axis
unsurmountable, unsaturable antagonist
y-axis decreases each time that same concentration used
Antagonist Assay: Binding Assay
incubate receptor with known agonist (traceable i.e. fluorescent, radioactive)
wash out extra agonist
,add antagonist
Antagonist Assay: Response Assay
quantify antagonist function
get dose response for agonist
repeat in presence of increasing antagonist concentrations
Dose ratio
quantification of the effect an antagonist has on response
DR= K'/K= EC50 with antagonist/ EC50 without antagonist
What does a higher pA2 mean?
antagonist is less potent because it requires a higher concentration
Competitive Binding Schild analysis
linear
Noncompetitive Binding Schild Analysis
y=x^2
will eventually block all receptors regardless of amount of agonist
Cooperative Binding Schild Analysis
looks like hook
think pirate "r"
Heterogeneous Binding Schild Analysis
blocks one receptor then blocks the other
Non-equilibrium Binding Schild Analysis
looks linear but slight bend at the top
Inverse agonists
binds to agonist and decreases response
needs constitutive activity
Constitutively active system
the more inverse agonist added amount of response decreases
, increase in agonist out competes inverse agonist = increase in response
No constitutive activity
inverse has nothing to decrease, is just competitive antagonist
Concerted Model
A conformational change in one subunit requires the same conformational change in all
subunits
Binding of an allosteric modulator to an allosteric site can shift the equilibrium between
the R or T forms which in turn can impact ligand binding to the orthosteric site
The R or T forms of the receptor might differentially activate or inhibit downstream
signaling
Sequential Model
Induced fit: The binding of a ligand to one subunit induces a conformational change in
the conformation of that subunit from the T to R state
The ligand-induced transition from T to R favours the binding of ligand to other subunits,
but does not obligate it
Advantages of Allosteric Drugs over Orthosteric Drugs
Do not need to outcompete the orthosteric ligand to be effective
Can be more drug-like than for example a protein/peptide orthosteric ligand
May allow greater selectivity between different receptors that are activated by the same
ligands
Allosteric Modulators may be Safer
They are inactive in the absence of the endogenous ligand
They don't disturb normal biological rhythms, less desensitization
Partial allosteric modulators may be achievable avoiding full receptor activation /
inhibition at even 100% occupancy of the allosteric modulator
They can be used in conjunction with orthosteric ligands
Allosteric Modulators Can
Offer new opportunities for drug discovery on a mature field
Allosteric Modulators GPCRs
Primarily changes the apparent affinity of the orthosteric ligand
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