AH Biology: Unit 1 Proteomics and Protein Structure 3 Binding to Ligands.
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Transcript of AH Biology: Unit 1 Proteomics and Protein Structure 3 Binding to Ligands.
AH Biology: Unit 1 Proteomics and Protein
Structure 3Binding to Ligands
Think
• How is protein production controlled?
• Why is it important that protein production is controlled?
• Why is protein structure important in relation to its function?
Binding to ligands
• A ligand is a substance that can bind to a protein.
• R groups not involved in protein folding can allow binding to these other molecules.
• Binding sites will have complementary shape and chemistry to the ligand.
• The ligand can either be a substrate or a molecule that affects the activity of the protein.
Nucleosomes
Nucleosomes
• Nucleosomes animation
• DNA replication animation
Transcription
• Other proteins have binding sites that are specific to particular sequences of double-stranded DNA and when bound to can either stimulate or inhibit initiation of transcription.
• lac Operon
• Transcription animation
Binding changes the conformation of a protein
• Enzymes and proteins are three-dimensional and have a specific shape or conformation.
• As a ligand binds to a protein binding site, or a substrate binds to an enzyme’s active site, the conformation of the protein changes.
• This change in conformation causes a functional change in the protein and may activate or deactivate it.
Induced fit
• In enzymes, specificity between the active site and substrate is related to induced fit.
• When the correct substrate starts to bind, a temporary change in shape of the active site occurs, increasing the binding and interaction with the substrate.
• Induced fit
Induced fit
Activation energy lowered
Allosteric enzymes
• An allosteric enzyme is an enzyme that can have its activity altered by a ligand called a modulator.
• In allosteric enzymes, modulators bind at secondary binding sites away from the active site.
• The conformation of the enzyme changes and this alters the affinity of the active site for the substrate.
Modulators
• Negative modulators reduce the enzyme’s affinity for the substrate.
• Positive modulators increase enzyme affinity for the substrate.
Negative modulators
Negative modulators
• End product inhibition occurs when the final product of a cascade of enzyme reactions interacts with an allosteric site of the first enzyme in the cascade to inhibit it and thus the production of the end product.
• This is an example of negative feedback.
• End product inhibition animation
Competitive inhibition
Competitive inhibition example 1
• Ethanol is metabolised in the body to acetaldehyde by oxidation with alcohol dehydrogenase, which is in turn further oxidised to acetic acid by aldehyde oxidase enzymes.
• Normally, the second reaction is rapid so acetaldehyde does not accumulate in the body.
• A drug called disulfiram (Antabuse) inhibits the aldehyde oxidase, which causes the accumulation of acetaldehyde with subsequent unpleasant side effects of nausea and vomiting.
• This drug is sometimes used to help people overcome alcoholism.
Competitive inhibition example 2
• Methanol poisoning occurs because methanol is oxidised to formaldehyde and formic acid, which attack the optic nerve and cause blindness.
• Ethanol is given as an antidote for methanol poisoning because ethanol competitively inhibits the oxidation of methanol.
• Ethanol is oxidised in preference to methanol and consequently the oxidation of methanol is slowed down and the toxic by-products do not have a chance to accumulate.
• The methanol is then excreted in the urine.
Competitive inhibition example 3
• Ethylene glycol, if ingested, can be poisonous.
• Ethylene glycol is oxidised by the same enzymes used in the previous two examples.
• Ethylene glycol → glycolaldehyde → glycolic acid.
• Glycolic acid is toxic to the nervous system and kidneys.
• Describe how ethanol can be used as an antidote.
Non-competitive inhibition
Enzyme kinetics and inhibition
Competitive inhibition
Competitive inhibition
• If the concentration of inhibitor is less than that of the substrate and the substrate has a higher affinity for the active site, is the enzyme inhibited a lot or a little?
• If the concentration of inhibitor is more than that of the substrate is the enzyme inhibited a lot or a little?
• If the enzyme is inhibited and we then increase the substrate concentration what happens to the initial rate of reaction?
Non-competitive inhibition
Competitive inhibition
Non-competitive inhibition
Enzyme kinetics and inhibition
Positive modulators
• Positive modulators increase the enzyme affinity for the substrate by altering the shape of the active site so that it has a better fit for the substrate.
• Positive modulation animation of a steroid on a GABAA receptor linked ion channel.
Enzyme kinetics questions
• Enzyme kinetics questions.
Cooperativity in haemoglobin
• Binding and release of oxygen in haemoglobin.
Cooperativity in hemoglobin• Deoxyhaemoglobin has a relatively low affinity for oxygen.
• As one molecule of oxygen binds to one of the four haem groups in a hemoglobin molecule it increases the affinity of the remaining three haem groups to bind oxygen.
• Conversely, oxyhaemoglobin increases its ability to loose oxygen as oxygen is released by each successive haem.
• This creates the classic sigmoid shape of the oxygen dissociation curve.
Cooperativity in haemoglobin
Effects of temperature and pH
• Low pH = low affinity.
• High temperature = low affinity.
• Exercise increases body temperature and produces CO2, acidifying the blood.
• This has a corresponding effect on the oxyhaemoglobin dissociation curve.
Bohreffect
Oxygen dissociation curve
• Oxygen dissociation review in relation to a patient admitted to hospital.
• What sort of conditions affect the ability of red blood cells to transport oxygen?
• Under what conditions would haemoglobin struggle to bind oxygen?
Red blood cell disorders
• Sickle cell anaemia
• Thalassaemia
High-altitude conditions
• High-altitude medicine
• High-altitude effects: BBC Horizon, ‘How to Kill a Human Being’
Think
• How is protein production controlled?
• Why is it important that protein production is controlled?
• Why is protein structure important in relation to its function?