Drug Targets Flashcards
what are the 7 types of drug target?
- Nuclear Hormone receptor (NHR)
- Enzyme
- voltage-gated ion channels
- tyrosine kinase receptor
- transporter (transport proteins)
- ligand-gated ion chanel
- G- Protein coupled receptor (GPCR)
How do transport proteins function?
By binding their substrate on one side of the membrane and then changing conformation to release the substrate on the opposite side
at what speed to transport proteins work?
up to 10000 substrates per second
are transport proteins active or passive?
both
What happens in facilitated diffusion?
the transport protein allows substrates to move passively downs its electrochemical gradient
Give an example of a primary active transport protein
Sodium-Potassium ATPase
Give an example of a secondary active transport protein
either
Na+, H+ exchange
or
Na+ and Glucose co transport
What’s faster ion channels or transport proteins?
Ion channels
how fast are ion channels?
can transport up to 1000000 substrates per second
what type of transport do ion channels allow?
passive (down the electrochemical gradient)
What are the basic properties of ion channels? (4)
- transmembrane
- selectively permeable
- opening controlled
- diverse
what is meant by ion channels being selectively permeable?
they select between various ions on the basis of size and charge
How do ion channels select on the basis of charge?
Around the mouths of some ion channels, there are amino acid rings with the opposite charge to the ion it’s selective for, therefore will only allow the correctly charged ions in (will repel those with the same charge)
what state are most ion channels in most the time?
closed
what is ion channel opening controlled by?- give 4
Any 4 from:
- mechanics
- 2nd messenger
- phosphorylation
- leak
- ligand-gated
- voltage-gated
- proton- gated
- temperature- gated
how are ion channels named/ classified?
By gating and ion-selectivity or the ligand they allow in
How many main families of ligand-gated ion channels are there?
2
What happens in both families of ligand-gated ion channels to open them?
They both have their opening controlled by the binding of at least 2 molecules of neurotransmitter, which induces a conformational change and the built-in ion channel opens allowing the ions to pass through
What’s a key example of a ligand-gated ion channel?
Muscle Nicotinic receptor
How many subunits does the Muscle nicotinic receptor have?
5
what are the 5 subunits of the muscle nicotinic recepto?
2 alphas, 1 beta, 1 delta and 1 epsilon
Where is the ion channel located in the muscle nicotinic receptor?
at the centre of the complex
Where are the acetylcholine binding sites in the muscle nicotinic receptor?
- between the alphas and their neighbouring delta and epsilon subunits
how many transmembrane domains does each muscle nicotinic receptor have?
4
Generally, what are voltage-gated ion channels?
Ion channels that open in response to changes in membrane potential (usually the membrane depolarizing)
what are the 3 main classes of voltage-gated ion channels?
calcium, sodium and potassium
How many subunits do most voltage-gated ion channels have?
4 (tetrameric)
in voltage-gated ion channels where is the channel located?
centre of the complex
What is the structure of Na+ and Ca2+ channels?
- formed from an alpha subunit and a smaller beta subunit. The alpha subunit can form the channel on its own and consists of 4 pseudosubunits with 6 transmembrane domains. The 4th TM domain is charge and acts as a voltage sensor
Are nuclear hormone receptors intracellular or extracellular?
intracellular
What is the basic NHR mechanism? (transactivation)
- Steroid hormone starts outside target cell.
- It is lipid-soluble so can easily slip through the membrane
- once inside the cell, it can interact with Glucocorticoid Receptors (GCR). These receptors are normally bound to Heat Shock Proteins (HSP)
- The interaction with the steroid causes the HSP to dissociate
- The GCR dimerizes and enters the nucleus through a nuclear pore (monomeric receptors can also enter the nucleus)
- After translocation into the nucleus, the NHR dimer binds to a section of DNA known are the Hormone Responsive Element (HRE)
- It’s then able to recruit coactivator proteins and RNA polymerase and promotes the transcription of mRNA and thus protein expression
This is TRANSACTIVATION
What happens during transrepression?
where GCR binding to a transcription factor inhibits transcription. The mechanism of this involves receptor monomers and the receptor doesn’t bind to DNA
What’s the most diverse receptor class?
G-Protein Coupled Receptors (GPCR)
Acetylcholine GPCRs can be what 2 types?
Muscularinic or Nicotinic
What are muscularinic receptors subdivided into?
M1,2,3,4,5
What are the adrenic receptor subtypes?
alpha 1, alpha 2, beta 1, beta 2
What’s the most useful/important drug class?
Those targetted at GPCRs
what’s the structure of GPCRs?
- 7 transmembrane domains
- NH2 terminus on the outside of cell
how do GPCRs function?
by translating an extracellular signal from a neurotransmitter/hormone into an intracellular second messenger. The 2nd messengers are small molecules that bind to proteins within the cell and alter its function
what components are required for a GPCR to function?
- agonist ligand
- GPCR (membrane bound)
- G-protein (trimeric and binds to GTP and GDP)
- a protein (usually an enzyme to generate 2nd messenger regulated by G-protein)
What happens during the G-protein activation cycle?
1) G-protein has GDP bound to it
2) agonist binds to GPCR. This allows the G-protein to interact with the GPCR. When this occurs, the G-Proteins bound GDP is replaced by GTP
3) the binding of GTP triggers the G-protein to split into 2 parts (alpha subunit with GTP and Beta-Gamma subunits). Both these parts are active
4) The alpha subunit has a built-in GTP-ase activity and eventually will hydrolyse GTP to GDP+Pi- terminating the signalling process
What do G-proteins often use as their intracellular second message?
cAMP
How is cAMP produced?
from ATP by the enzyme adenylate cyclase
What’s the main effect of cAMP?
to switch protein kinases from an inactive to active conformation
what inhibits cAMP?
Gi (G-protein)
What’s the IP3 pathway?
a second very important signalling system coupled to IP3 production via the actions of phospholipase C
What does IP3 stand for?
Inasitol tris Phosphate
What is IP3?
the phosphosugar head group of the lipid phosphatidylinositol bis phosphate
Give an example of signals coupled to IP3/Phospholipase C
one of:
- Acetylcholine (muscarinic receptor)
- adrenaline/noradrenaline
- serotonin
What’s the function of phospholipase C split into?
2 parts- a) diacyl glycerol (DAG)- the glycerol section with 2 fatty acid chains attached
b) the head group IP3
What can the 2 parts of of phospholipase be used for?
a second messenger
What are orphan receptors?
receptors identified from their gene sequence as belonging to particular receptor families, however the natural ligand hasn’t been identified, so the physiological role is unknown
Why are orphan receptors so important for the pharma industry?
Could allow companies to find a target that no one else has worked on
What is the G protein Gq coupled to?
Phospholipase C
What is the G protein Gs coupled to?
Adenylate Cyclase
Which G proteins are coupled to adenylate cyclase?
Gi and Gs
which of the following ISN'T a characteristic of a ligand- gated ion channel? Hydrophobic membrane spanning domains GTPase activity an extracellular agonist binding site a large intracellular loop
GTPase activity
How many points of attachment does noradrenaline make to adrenergic receptors?
3
What binds more tightly to the B2- adrenoreceptor- R- adrenaline or S-adrenaline?
R-adrenaline
What type of drug target is an adrenergic receptor?
GPCR
What type of drug target is a dopamine receptor?
GPCR
What type of drug target is a Somatostatin receptor?
GPCR
what type of drug target is a progesterone receptor
NHR
