CHEM2052 Tutorial Example4 - Revision history

Avril Robertson at 08:51, 13 August 2014

2014-08-13T08:51:49Z

← Older revision		Revision as of 08:51, 13 August 2014
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	Similarly this view shows the amino acid residues on the		Similarly this view shows the amino acid residues on the
	<scene name='59/596437/Lhs_aminoacids_representation/2'>~~right~~ hand side</scene> of your "map".		<scene name='59/596437/Lhs_aminoacids_representation/2'>left hand side</scene> of your "map". Again you can view this with the atoms of the inhibitor colour coded
			<scene name='59/596437/Lhs_aminoacids_representation/3'>find it here</scene>.

	~~== Structural highlights ==~~

	This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.



	~~</StructureSection>~~
	== References ==		== References ==
	<references/>		<references/>

Avril Robertson at 08:48, 13 August 2014

2014-08-13T08:48:18Z

← Older revision		Revision as of 08:48, 13 August 2014
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	This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/2'>right hand side</scene> of your "map". You should notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor. If you prefer to view the structure where the inhibitor atoms are colour coded you will <scene name='59/596437/Renin_interactions_rhs_again/1'>find it here. </scene>		This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/2'>right hand side</scene> of your "map". You should notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor. If you prefer to view the structure where the inhibitor atoms are colour coded you will <scene name='59/596437/Renin_interactions_rhs_again/1'>find it here. </scene>

	Similarly this view shows the amino acid residues on the right hand side of your "map".		Similarly this view shows the amino acid residues on the
			<scene name='59/596437/Lhs_aminoacids_representation/2'>right hand side</scene> of your "map".

	== Structural highlights ==		== Structural highlights ==

Avril Robertson at 08:39, 13 August 2014

2014-08-13T08:39:07Z

← Older revision		Revision as of 08:39, 13 August 2014
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	This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.		This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.

	This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/2'>right hand side</scene> of your "map". You should notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.		This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/2'>right hand side</scene> of your "map". You should notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor. If you prefer to view the structure where the inhibitor atoms are colour coded you will <scene name='59/596437/Renin_interactions_rhs_again/1'>find it here. </scene>

	Similarly this view shows the amino acid residues on the right hand side of your "map".		Similarly this view shows the amino acid residues on the right hand side of your "map".

Avril Robertson at 08:34, 13 August 2014

2014-08-13T08:34:01Z

← Older revision		Revision as of 08:34, 13 August 2014
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	This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.		This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.

	This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/1'>~~left~~ hand side</scene> of your "map". You ~~may~~ notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.		This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/2'>right hand side</scene> of your "map". You should notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.

	Similarly this view shows the amino acid residues on the right hand side of your "map".		Similarly this view shows the amino acid residues on the right hand side of your "map".

Avril Robertson at 08:27, 13 August 2014

2014-08-13T08:27:38Z

← Older revision		Revision as of 08:27, 13 August 2014
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	This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.		This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.

	This view shows the amino acid residues on the left hand side of your "map". You may notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.		This view shows the amino acid residues on the <scene name='59/596437/Renin_interactions_rhs/1'>left hand side</scene> of your "map". You may notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.

	Similarly this view shows the amino acid residues on the right hand side of your "map".		Similarly this view shows the amino acid residues on the right hand side of your "map".

Avril Robertson at 08:19, 13 August 2014

2014-08-13T08:19:08Z

← Older revision		Revision as of 08:19, 13 August 2014
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	== '''Chem2052: Example 4 - Renin''' ==		== '''Chem2052: Example 4 - Renin''' ==

	The spinning structure you initially view on this page is a protease called Renin. Renin is an '''aspartyl protease''', which cleaves a particular peptide called angiotensinogen.		The spinning structure you initially view on this page is a protease called '''Renin''' (also known as '''angiotensinase'''). Renin is an '''aspartyl protease''', which cleaves a particular peptide called angiotensinogen. Although this enzyme functions as a monomer the crystal structure obtained is a dimer and this is what you can see here. In the following representations one of the sub-units has been removed to represent the protein in its natural state.

	== '''Background''' ==		== '''Background''' ==

	In later lecture we will look a little more closely at '''Renin''' ~~(also known as '''angiotensinase''')~~. This enzyme is involved in a biological pathway leading to elevation of blood pressure, which can be beneficial in many ways. However if this process has become overactive, hypertension (high blood pressure) can result. Hypertension leads to cardiovascular disease which is the leading cause of death globally. The World Health Organisation states "An estimated 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths" see the following web page if you want to know more: [http://www.who.int/mediacentre/factsheets/fs317/en/ Cardiovascular disease facts WHO].		In later lecture we will look a little more closely at '''Renin'''. This enzyme is involved in a biological pathway leading to elevation of blood pressure, which can be beneficial in many ways. However if this process has become overactive, hypertension (high blood pressure) can result. Hypertension leads to cardiovascular disease which is the leading cause of death globally. The World Health Organisation states "An estimated 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths" see the following web page if you want to know more: [http://www.who.int/mediacentre/factsheets/fs317/en/ Cardiovascular disease facts WHO].

	Since the 1970s scientists have been trying to modulate the action of renin by blocking the active site of the enzyme and preventing its function, hence lowering blood pressure. Aliskerin is the only renin inhibitor in clinical use today [http://en.wikipedia.org/wiki/Renin_inhibitor Renin information Site]. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<ref>PMID:17574423</ref>		Since the 1970s scientists have been trying to modulate the action of renin by blocking the active site of the enzyme and preventing its function, hence lowering blood pressure. Aliskerin is the only renin inhibitor in clinical use today [http://en.wikipedia.org/wiki/Renin_inhibitor Renin information Site]. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<ref>PMID:17574423</ref>

Avril Robertson at 08:15, 13 August 2014

2014-08-13T08:15:27Z

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	== '''Active Site Interactions''' ==		== '''Active Site Interactions''' ==

	~~Once you have thought about~~ the ~~types of interactions you would expect this inhibitor COULD make~~ at the active site of the enzyme ~~(refer to your notes for an example)then~~ look at the 2-dimensional "map" of the active site on your tutorial sheet and compare this to the 3-dimensional representations here.		This inhibitor does not just bind to the catalytic residues there are many other amino acids at the active site of the enzyme. First predict possible interaction types you would expect with this structure. Then look at the 2-dimensional "map" of the active site provided on your tutorial sheet and compare this to the 3-dimensional representations here.

	This view shows the amino acid residues on the left hand side of your "map".		This view shows the amino acid residues on the left hand side of your "map". You may notice that these amino acids are fairly hydrophobic and interact with the hydrophobic parts of the inhibitor.

	~~This~~ view shows the amino acid residues on the right hand side of your "map".		Similarly this view shows the amino acid residues on the right hand side of your "map".

	== Structural highlights ==		== Structural highlights ==

Avril Robertson at 08:09, 13 August 2014

2014-08-13T08:09:28Z

← Older revision		Revision as of 08:09, 13 August 2014
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	== '''Active Site''' ==		== '''Active Site''' ==

	This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin. Consider the mechanism of the enzymatic cleavage of the natural peptide substrate ~~angiotensinase~~. Identify the structure of the transition state. In later lectures we will see how knowledge of this transition state can be used to design very effective enzyme inhibitors which mimic this structure, as you will find out, these are (not surprisingly) called "transition state" inhibitors. But for now though we will focus on the Pfizer inhibitor.		This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin. Consider the mechanism of the enzymatic cleavage of the natural peptide substrate by the catalytic residues [http://www.cambridgemedchemconsulting.com/resources/hit_identification/aspartic_protease_inhibitors.html you will find it here]. Identify the structure of the transition state. In later lectures we will see how knowledge of this transition state can be used to design very effective enzyme inhibitors which mimic this structure, as you will find out, these are (not surprisingly) called "transition state" inhibitors. But for now though we will focus on the Pfizer inhibitor.

	== '''Inhibition of Renin''' ==		== '''Inhibition of Renin''' ==

Avril Robertson at 07:57, 13 August 2014

2014-08-13T07:57:43Z

← Older revision		Revision as of 07:57, 13 August 2014
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	Once you have thought about the types of interactions you would expect this inhibitor COULD make at the active site of the enzyme (refer to your notes for an example)then look at the 2-dimensional "map" of the active site on your tutorial sheet and compare this to the 3-dimensional representations here.		Once you have thought about the types of interactions you would expect this inhibitor COULD make at the active site of the enzyme (refer to your notes for an example)then look at the 2-dimensional "map" of the active site on your tutorial sheet and compare this to the 3-dimensional representations here.

	This view shows the amino acid residues on the left hand side of your "map".		This view shows the amino acid residues on the left hand side of your "map".

	This view shows the amino acid residues on the right hand side of your "map".		This view shows the amino acid residues on the right hand side of your "map".

Avril Robertson at 07:56, 13 August 2014

2014-08-13T07:56:11Z

← Older revision		Revision as of 07:56, 13 August 2014
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	The spinning structure you initially view on this page is a protease called Renin. Renin is an '''aspartyl protease''', which cleaves a particular peptide called angiotensinogen.		The spinning structure you initially view on this page is a protease called Renin. Renin is an '''aspartyl protease''', which cleaves a particular peptide called angiotensinogen.

	== Background ==		== '''Background''' ==

	In later lecture we will look a little more closely at '''Renin''' (also known as '''angiotensinase'''). This enzyme is involved in a biological pathway leading to elevation of blood pressure, which can be beneficial in many ways. However if this process has become overactive, hypertension (high blood pressure) can result. Hypertension leads to cardiovascular disease which is the leading cause of death globally. The World Health Organisation states "An estimated 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths" see the following web page if you want to know more: [http://www.who.int/mediacentre/factsheets/fs317/en/ Cardiovascular disease facts WHO].		In later lecture we will look a little more closely at '''Renin''' (also known as '''angiotensinase'''). This enzyme is involved in a biological pathway leading to elevation of blood pressure, which can be beneficial in many ways. However if this process has become overactive, hypertension (high blood pressure) can result. Hypertension leads to cardiovascular disease which is the leading cause of death globally. The World Health Organisation states "An estimated 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths" see the following web page if you want to know more: [http://www.who.int/mediacentre/factsheets/fs317/en/ Cardiovascular disease facts WHO].
Line 13:		Line 13:
	== '''Active Site''' ==		== '''Active Site''' ==

	This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin. Consider the mechanism of the enzymatic cleavage of the natural peptide substrate angiotensinase. Identify the structure of the transition state. In later lectures we will see how knowledge of ~~the~~ transition state can be used to design very effective enzyme inhibitors which mimic this ~~transition state~~ these are (not surprisingly) called "transition state" inhibitors.		This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin. Consider the mechanism of the enzymatic cleavage of the natural peptide substrate angiotensinase. Identify the structure of the transition state. In later lectures we will see how knowledge of this transition state can be used to design very effective enzyme inhibitors which mimic this structure, as you will find out, these are (not surprisingly) called "transition state" inhibitors. But for now though we will focus on the Pfizer inhibitor.

	== '''Inhibition of Renin''' ==		== '''Inhibition of Renin''' ==

	This scene shows the <scene name='55/559112/Renin_catalytic_residues/1'>active site of renin with the Pfizer inhibitor bound</scene>. Which part of the inhibitor binds to the catalytic residues of the active site?		This scene shows the <scene name='55/559112/Renin_catalytic_residues/1'>active site of renin with the Pfizer inhibitor bound</scene>. Which part of the inhibitor binds to the catalytic residues of the active site?

			== '''Active Site Interactions''' ==

			Once you have thought about the types of interactions you would expect this inhibitor COULD make at the active site of the enzyme (refer to your notes for an example)then look at the 2-dimensional "map" of the active site on your tutorial sheet and compare this to the 3-dimensional representations here.
			This view shows the amino acid residues on the left hand side of your "map".
			This view shows the amino acid residues on the right hand side of your "map".

	== Structural highlights ==		== Structural highlights ==