Drug Targets - 3

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  • Created by: LBCW0502
  • Created on: 26-09-19 11:13
Describe the structure and function of receptors (1)
Proteins act as cell's 'letter boxes/message reception'. Located mostly in cell membrane but some intracellular. Receive messages from chemical messengers coming from other cells (hormones, neurotransmitters)
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Describe the structure and function of receptors (2)
Transmit message into cell leading to a cellular effect. Different receptors specific for different chemical messengers. Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
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Describe the structure and function of receptors (3)
Messengers diffuse across the synapse to the receptor. Typical neurone will have 1000s of receptors, not just one. Fine control of complex neural pathways
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What are the two types of chemical messengers?
Neurotransmitters and hormones
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What are neurotransmitters?
Chemical released from nerve endings which travel the short distance across a nerve synapse to bind with receptors on target cells such as muscle cells or another nerve. Responsible for messages between individual nerve cells (short lived response)
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What are hormones?
Chemicals released from cells or glands which can travel some considerable distance to bind with receptors on various target cells throughout the body
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What is the function of chemical messengers?
Switch on receptors without undergoing a reaction (unlike substrates for enzymes)
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Give examples of neurotransmitters
GABA, dopamine, 5HT
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Give examples of hormones
Oestrogen, encephalin (many hormones are peptides)
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Describe the structure of receptors (1)
(On/off switch). Contain binding site (analogous to active site in an enzyme) that the chemical messenger binds to. Binding involves non-covalent intermolecular bonds
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Describe the structure of receptors (2)
Binding results in an induced fit of the receptor protein and a conformational change in the receptor. Conformational change in the receptor shape results in conformational change/dissociation of non-covalently attached enzyme
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Describe the structure of receptors (3)
Results in enzyme activation. Domino effect (signal transduction) leads to chemical signal being received inside cell from enzyme. Chemical messenger doesn't enter cell but departs receptor unchanged and is not permanently bound
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Describe how receptor binding leads to intracellular changes via a cascade effect (1)
Chemical messenger binds to GPCR. Conformational change in receptor causes non-covalently attached proteins to dissociate and diffuse away. One of the proteins bind non-covalently to an enzyme (PLC)
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Describe how receptor binding leads to intracellular changes via a cascade effect (2)
Enzyme activation causes further downstream changes in the cell. 1 signal molecule can stimulate enzymic formation of 1000s of internal biochemicals. Cascade/Domino effect
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Describe how the signal molecule and receptor interact to turn the signal off
Binding temporary and after a period of time (residence time) messenger diffuses away. In synapses, the neurotransmitters return to the original neurone (re-uptake). All movement of molecules is achieved by diffusion
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Describe how signal transduction works
Receptor might also be the enzyme. Protein has dual role (receptor and enzyme). Receptor binds messenger leading to an induced fit. Protein changes shape and opens active site. Reaction catalysed within cell
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Describe features of the binding site
A hollow or cleft on the receptor surface (equivalent to active site of enzyme). Accepts and binds (non-covalently) to a chemical messenger. Contains amino acids which bind the messenger. No reaction or catalysis takes place, unlike with enzymes
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How does messenger binding work? (1)
Binding site is nearly the correct shape for the messenger. Binding alters the shape of the receptor (induced fit). Altered receptor shape leads to further effects - signal transduction
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How does messenger binding work? (2)
Messenger binding is non-covalent
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Outline the overall process of receptor-messenger interaction
Binding interactions must be strong enough to hold messenger sufficiently long for signal transduction to take place and weak enough to allow messenger to depart. Fine balance (too long and overstimulation occurs)
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What are an agonist? (1)
Binds reversibly to the binding site. Similar intermolecular bonds formed as to natural messenger. Induced fit alters shape of the receptor in the same way as the normal messenger. Receptor is activated
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What are an agonist? (2)
Agonists are often similar in structure to the natural messenger
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Give an example of an agonist (1)
Diabetes drug (synthetic drug agonist). Activation of receptor GPR-40 releases insulin. Natural agonists are long chain fatty acids. Synthetic agonists used to stimulate insulin secretion. More antagonist drugs than agonists
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Give an example of an agonist (2)
Agonist drugs can lead to overstimulation and side effects
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How do you interfere with processes to treat a disease? (1)
A compound that turns a receptor on is called an agonist. Natural chemical messengers are agonists. Unnatural chemical that have the same effect are also agonists. Unnatural chemical that binds but doesn't turn on receptor are called antagonists
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How do you interfere with processes to treat a disease? (2)
Antagonists prevent agonists binding and prevent any response. Many drugs are antagonists - they tone down an overactive physiological process
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How do antagonists achieve a reduction in overactivity of a physiological process at the molecular level? (1)
Antagonists bind to the receptor but don't induce conformational change. E.g. 5HT antagonists (risperidone, clozapine, ondansetron, spiperone). Structural differences between themselves and to 5HT
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How do antagonists achieve a reduction in overactivity of a physiological process at the molecular level? (2)
All bind to 5HT receptor without inducing conformational change required for activation. Ondansetron (prevents vomiting, used in anti-cancer treatment)
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Describe the control of ion channels (which is another response to signal transduction) (1)
Receptor protein can sometimes be linked to an ion channel protein complex. Receptor binds a messenger leading to an induced fit. Ion channel is then opened or closed due to conformational change
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Describe the control of ion channels (which is another response to signal transduction) (2)
Ion channels are specific for specific ions (Na+, Ca 2+, Cl-, K+). Ions flow across cell membrane down concentration gradient. Polarises or depolarises nerve membranes
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Describe the structure of ion channels
Hydrophobic tunnel is lined with polar/charged amino acid. Generally filled with water. Constriction point in the middle can select for charge and size
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What are two types of ion channels?
Cationic ion channels for K+, Na+, Ca2+ (e.g. nicotine) - excitatory. Anionic ion channels for Cl- (GABA-A) - inhibitory
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Describe the structure of the GABA-A receptor
Pentameric complex of 5 proteins. Opened by GABA. Cl- ions pass into cell opening. (Ion channels are often complex multimeric structures of the same or very similar protein)
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Give an example of an intracellular receptor
Cortisol diffuses into cell. Lipophilic molecules pass through cell membrane easily. Binds to receptor in cytoplasm. Cortisol/receptor complex passes into nucleus. Complex interacts with DNA to affect transcription
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Describe features of non-competitive allosteric antagonists (1)
No allosteric antagonist and agonist binds (receptor activated). Allosteric antagonist binds, agonist cannot bind (receptor deactivated)
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Describe features of non-competitive allosteric antagonists (2)
Allosteric antagonists are able to bind at a different site on the receptor, remote from the usual messenger binding site and alter the conformation of the receptor such that the antagonist cannot bind
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Give an example of a non-competitive allosteric antagonist (1)
GSK812397, non-competitive antagonist of CXCR4 receptor. Natural agonist is a peptide called SDF1. HIV virus binds to agonist site as part of entry process. GSK812397 bind to allosteric site and prevents binding to agonist site
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Give an example of a non-competitive allosteric antagonist (2)
GSK812397 protects human cells against HIV infection
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Summarise features of drug targets (1)
Drug targets are usually proteins (can be DNA). Binding of molecule to protein involves non-covalent interactions (hydrophobic interactions, H bonds, ionic interactions). Enzymes - substrate molecule undergoes reactions and product is released
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Summarise features of drug targets (2)
Inhibitor molecule remains unchanged (sometimes irreversibly covalently binds to enzyme). Receptors - no chemical reaction of ligand (natural messenger is an agonist/turns receptor on). Unnatural agonists (useful as drugs)
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Summarise features of drug targets (3)
Antagonists bind to receptor but don't activate. Many drugs are antagonists of receptors. Allosteric drugs act remotely from normal site on protein
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Transmit message into cell leading to a cellular effect. Different receptors specific for different chemical messengers. Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers

Card 3

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Describe the structure and function of receptors (3)

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Card 4

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Card 5

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