https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Avril+RobertsonProteopedia - User contributions [en]2026-09-16T18:30:23ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=2427853CHEM2052 Tutorial2015-08-18T00:19:45Z<p>Avril Robertson: </p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='59/596400/Morph/3'>trypsin catalytic triad and the elastase catalytic triad</scene> (<span style="color:lightblue;background-color:black;font-weight:bold;">trypsin is in light blue</span>, PDB code [[1aq7]] and <span style="color:pink;background-color:black;font-weight:bold;">elastase is in pink</span>, PDB code [[4est]]). <jmol><jmolButton><script>frame next</script><text>Click this button</text></jmolButton></jmol> to flip between structures.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
The following animation describes the catalytic mechanism of chymotrypsin [http://www.sumanasinc.com/webcontent/animations/content/chymotrypsin.html]. <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as hemoglobin. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
==3D structures of chymotrypsin==<br />
<br />
[[Chymotrypsin]]<br />
<br />
==3D structures of trypsin==<br />
<br />
[[Trypsin]]<br />
<br />
==3D structures of elastase==<br />
<br />
[[Elastase]]<br />
----<br />
<br />
<br />
==References==<br />
<references /></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=2427852CHEM2052 Tutorial2015-08-17T23:42:51Z<p>Avril Robertson: </p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='59/596400/Morph/3'>trypsin catalytic triad and the elastase catalytic triad</scene> (<span style="color:lightblue;background-color:black;font-weight:bold;">trypsin is in light blue</span>, PDB code [[1aq7]] and <span style="color:pink;background-color:black;font-weight:bold;">elastase is in pink</span>, PDB code [[4est]]). <jmol><jmolButton><script>frame next</script><text>Click this button</text></jmolButton></jmol> to flip between structures.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
An animation of the hydrolysis reaction catalysed by chymotrypsin is shown in the following link [http://www.sumanasinc.com/webcontent/animations/content/chymotrypsin.html] <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as hemoglobin. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
==3D structures of chymotrypsin==<br />
<br />
[[Chymotrypsin]]<br />
<br />
==3D structures of trypsin==<br />
<br />
[[Trypsin]]<br />
<br />
==3D structures of elastase==<br />
<br />
[[Elastase]]<br />
----<br />
<br />
<br />
==References==<br />
<references /></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=2427851CHEM2052 Tutorial2015-08-17T23:40:38Z<p>Avril Robertson: </p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='59/596400/Morph/3'>trypsin catalytic triad and the elastase catalytic triad</scene> (<span style="color:lightblue;background-color:black;font-weight:bold;">trypsin is in light blue</span>, PDB code [[1aq7]] and <span style="color:pink;background-color:black;font-weight:bold;">elastase is in pink</span>, PDB code [[4est]]). <jmol><jmolButton><script>frame next</script><text>Click this button</text></jmolButton></jmol> to flip between structures.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
An animation of the hydrolysis reaction catalysed by chymotrypsin is shown in the following link [http://www.sumanasinc.com/webcontent/animations/content/chymotrypsin.html, animated version] <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as hemoglobin. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
==3D structures of chymotrypsin==<br />
<br />
[[Chymotrypsin]]<br />
<br />
==3D structures of trypsin==<br />
<br />
[[Trypsin]]<br />
<br />
==3D structures of elastase==<br />
<br />
[[Elastase]]<br />
----<br />
<br />
<br />
==References==<br />
<references /></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970629CHEM2052 Tutorial Example42014-08-13T08:51:49Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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><br />
<br />
Similarly this view shows the amino acid residues on the <br />
<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 <br />
<scene name='59/596437/Lhs_aminoacids_representation/3'>find it here</scene>.<br />
<br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970626CHEM2052 Tutorial Example42014-08-13T08:48:18Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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><br />
<br />
Similarly this view shows the amino acid residues on the <br />
<scene name='59/596437/Lhs_aminoacids_representation/2'>right hand side</scene> of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970625CHEM2052 Tutorial Example42014-08-13T08:39:07Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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><br />
<br />
Similarly this view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970624CHEM2052 Tutorial Example42014-08-13T08:34:01Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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.<br />
<br />
Similarly this view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970623CHEM2052 Tutorial Example42014-08-13T08:27:38Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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.<br />
<br />
Similarly this view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970621CHEM2052 Tutorial Example42014-08-13T08:19:08Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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.<br />
<br />
Similarly this view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970578CHEM2052 Tutorial Example42014-08-13T08:15:27Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
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.<br />
<br />
Similarly this view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970470CHEM2052 Tutorial Example42014-08-13T08:09:28Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
This view shows the amino acid residues on the left hand side of your "map".<br />
<br />
This view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970344CHEM2052 Tutorial Example42014-08-13T07:57:43Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
<br />
This view shows the amino acid residues on the left hand side of your "map".<br />
<br />
This view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970338CHEM2052 Tutorial Example42014-08-13T07:56:11Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== '''Background''' ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== '''Active Site Interactions''' ==<br />
<br />
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.<br />
This view shows the amino acid residues on the left hand side of your "map".<br />
This view shows the amino acid residues on the right hand side of your "map".<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970182CHEM2052 Tutorial Example42014-08-13T07:40:09Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970174CHEM2052 Tutorial Example42014-08-13T07:38:57Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
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 called "transition state" inhibitors.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1970165CHEM2052 Tutorial Example42014-08-13T07:35:18Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969767CHEM2052 Tutorial Example42014-08-13T05:41:20Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin.<br />
<br />
== '''Inhibition of Renin''' ==<br />
<br />
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?<br />
<br />
<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969766CHEM2052 Tutorial Example42014-08-13T05:38:31Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Site''' ==<br />
<br />
This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin.<br />
<br />
== '''Inhibition of Renin''' ==<br />
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 inhibibtor binds to the catalytic residues of the active site?<br />
<br />
<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969765CHEM2052 Tutorial Example42014-08-13T05:33:05Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
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.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Sites''' ==<br />
<br />
This representation illustrates the <scene name='59/596437/Renin_catalytic_residues/2'>active site catalytic residues</scene> of Renin.<br />
<br />
== '''Inhibition of Renin''' ==<br />
This scene shows the <scene name='55/559112/active site of renin with the Pfizer inhibitor bound/1'>Renin Catalytic Residues</scene>. Which part of the inhibibtor binds to the catalytic residues of the active site?<br />
<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=File:Renin_Monomer.pdb&diff=1969764File:Renin Monomer.pdb2014-08-13T05:17:43Z<p>Avril Robertson: Renin_2i4q_monomer</p>
<hr />
<div>Renin_2i4q_monomer</div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969763CHEM2052 Tutorial Example42014-08-13T04:41:19Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
The spinning structure you initially view on this page is an enzyme called Renin. Renin is an '''aspartyl protease''', like other proteases Renin cleaves peptides.<br />
<br />
== Background ==<br />
<br />
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].<br />
<br />
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><br />
<br />
== '''Active Sites''' ==<br />
<br />
This representation illustrates the active site catalytic residues of Renin.<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969762CHEM2052 Tutorial Example42014-08-13T04:39:49Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
The spinning structure you initially view on this page is an enzyme called Renin. Renin is an '''aspartyl protease''', like other proteases Renin cleaves peptides.<br />
<br />
== Background ==<br />
<br />
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/].<br />
<br />
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><br />
<br />
== '''Active Sites''' ==<br />
<br />
This representation illustrates the active site catalytic residues of Renin.<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969761CHEM2052 Tutorial Example42014-08-13T04:25:25Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 4 - Renin''' ==<br />
<br />
== Background ==<br />
<br />
In later lecture we will look at an enzyme called '''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/].<br />
<br />
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.<br />
<br />
== '''Active Sites''' ==<br />
<br />
This representation illustrates the active site catalytic residues of Renin.<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969738CHEM2052 Tutorial Example42014-08-12T06:20:31Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2i4q' size='450' side='right' caption='Renin (PDB code [[2i4q]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
<br />
== Background ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor Renin Wikipedia Site] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969737CHEM2052 Tutorial Example42014-08-12T06:19:38Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='2iq4' size='450' side='right' caption='Renin (PDB code [[2iq4]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
<br />
== Background ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor Renin Wikipedia Site] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969736CHEM2052 Tutorial Example42014-08-12T06:14:22Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<br />
<scene name='55/559112/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
<br />
== Background ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor Renin Wikipedia Site] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=File:2I4Q_Monomer.pdb&diff=1969735File:2I4Q Monomer.pdb2014-08-12T05:55:39Z<p>Avril Robertson: </p>
<hr />
<div></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969698CHEM2052 Tutorial Example42014-08-07T12:56:01Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
<br />
<br />
== Background ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor Renin Wikipedia Site] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Active Site and Mechanism ==<br />
<br />
== Inhibitors ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969697CHEM2052 Tutorial Example42014-08-07T12:53:51Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor Renin Wikipedia Site] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969696CHEM2052 Tutorial Example42014-08-07T12:45:35Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969695CHEM2052 Tutorial Example42014-08-07T12:44:50Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
Since the 1970s [http://en.wikipedia.org/wiki/Renin_inhibitor] 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. However there is still interest in developing new, improved inhibitors. This question looks at a renin inhibitor identified through research at Pfizer.<br />
<br />
<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969694CHEM2052 Tutorial Example42014-08-07T12:37:45Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
In later lecture we will look at an enzyme called 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/].<br />
<br />
It is possible to prevent the action of renin by blocking the active site of the enzyme and preventing its function, hence lowering blood pressure. Indeed many people have investigated this as a therapeutic option to treat hypertension.<br />
<br />
<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1969693CHEM2052 Tutorial Example42014-08-07T12:28:43Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
In later lecture we will look at an enzyme called Renin (also known as angiotensinase). The activity of this enzyme leads to elevation of blood pressure which can be beneficial in many settings. 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 CVDs in 2008, representing 30% of all global deaths" see the following web page if you want to know more: <br />
<br />
Inibitors of Renin can be used to treat hypertension (high blood pressure).<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=1969692CHEM2052 Tutorial2014-08-07T11:31:02Z<p>Avril Robertson: </p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/10'>trypsin catalytic triad</scene> and the <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/8'>elastase catalytic triad</scene>.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
Lehninger's Principles of Biochemistry (5th edition)describes the catalytic mechanism of chymotrypsin on pages 208-209. An [http://bcs.whfreeman.com/lehninger5e/pages/bcs-main.asp?v=&s=06000&n=00010&i=06010.01&o=|00610|00580|00590|00510|00540|00600|00550|00570|00630|00010|00020|00030|00040|00070|00080|00090|00100|01000|02000|03000|04000|05000|06000|07000|08000|09000|10000|11000|12000|13000|14000|15000|16000|17000|18000|19000|20000|21000|22000|23000|24000|25000|26000|27000|28000|99000| animated version] of the enzyme-catalyzed hydrolysis reaction is also available on the textbook's website. <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as hemoglobin. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
==3D structures of chymotrypsin==<br />
<br />
[[Chymotrypsin]]<br />
<br />
==3D structures of trypsin==<br />
<br />
[[Trypsin]]<br />
<br />
==3D structures of elastase==<br />
<br />
[[Elastase]]<br />
----<br />
<br />
<br />
==References==<br />
<references /></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1967170CHEM2052 Tutorial Example42014-08-06T11:34:54Z<p>Avril Robertson: </p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
<scene name='59/596437/Renin_catalytic_residues/1'>Renin Catalytic Residues</scene><br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial_Example4&diff=1967169CHEM2052 Tutorial Example42014-08-06T11:10:14Z<p>Avril Robertson: New page: ==CHEM2052_Tutorial_Example4== <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a default text for your page '''CHEM2052 Tutoria...</p>
<hr />
<div>==CHEM2052_Tutorial_Example4==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''CHEM2052 Tutorial Example4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=1967096CHEM2052 Tutorial2014-08-04T12:15:25Z<p>Avril Robertson: </p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
*<scene name='59/596400/Chymotrypsin_residues/1'>chymotrypsin-triad</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/10'>trypsin catalytic triad</scene> and the <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/8'>elastase catalytic triad</scene>.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
[http://www.whfreeman.com/newcatalog.aspx?search=Lehninger&isbn=071677108X Lehninger's Principles of Biochemistry (5th edition)] describes the catalytic mechanism of chymotrypsin on pages 208-209. An [http://bcs.whfreeman.com/lehninger5e/pages/bcs-main.asp?v=&s=06000&n=00010&i=06010.01&o=|00610|00580|00590|00510|00540|00600|00550|00570|00630|00010|00020|00030|00040|00070|00080|00090|00100|01000|02000|03000|04000|05000|06000|07000|08000|09000|10000|11000|12000|13000|14000|15000|16000|17000|18000|19000|20000|21000|22000|23000|24000|25000|26000|27000|28000|99000| animated version] of the enzyme-catalyzed hydrolysis reaction is also available on the textbook's website. <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as [http://www.pdb.org/pdb/explore/explore.do?structureId=1GZX hemoglobin]. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
To view the full, unmodified structures in the [http://www.pdb.org/pdb/home/home.do RSCB Protein Data Bank], here are links to each of the crystal structures shown above: [http://www.pdb.org/pdb/explore/explore.do?structureId=2cha chymotrypsin (2cha)], [http://www.pdb.org/pdb/explore/explore.do?structureId=1aq7 trypsin (1aq7)] and [http://www.pdb.org/pdb/explore/explore.do?structureId=4est elastase (4est)]. Keep in mind that these are only representative structures of each serine protease. Other structures can be found at the following links:<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=7GCH chymotrypsin (7gch)] This structure is shown in Figure 6-18 (page 206) of [http://www.whfreeman.com/newcatalog.aspx?search=Lehninger&isbn=071677108X Lehninger's Principles of Biochemistry (5th edition)].<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=1acb chymotrypsin (1acb)] This structure includes a bound protein, showing how the peptide fits into the active site of the enzyme.<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=2cmy trypsin (2cmy)] <br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=3est elastase (3est)] <br />
<br />
==3D structures of chymotrypsin==<br />
<br />
[[Chymotrypsin]]<br />
<br />
==3D structures of trypsin==<br />
<br />
[[Trypsin]]<br />
<br />
==3D structures of elastase==<br />
<br />
[[Elastase]]<br />
----<br />
<br />
<br />
==References==<br />
<references /></div>Avril Robertsonhttps://proteopedia.org/index.php?title=CHEM2052_Tutorial&diff=1967010CHEM2052 Tutorial2014-08-03T11:32:30Z<p>Avril Robertson: New page: <StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code 2cha)'> == '''Chem2052: Example 3 - S...</p>
<hr />
<div><StructureSection load='' size='450' side='right' scene='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2' caption='α-chymoptrypsin (PDB code [[2cha]])'><br />
== '''Chem2052: Example 3 - Serine Proteases''' ==<br />
<br />
'''Serine proteases''' account for over one-third of all known proteolytic enzymes <ref>PMID:17991683</ref>,<ref name="DiCera">PMID:19180666</ref>. Within the diverse collection of serine proteases, the most famous members are trypsin, chymotrypsin and elastase. Aside from their key roles in digestion (and other physiological processes) <ref name ="DiCera"/>, the unique specificities of these enzymes make them useful tools in biochemistry and molecular biology to ascertain protein sequences. <br />
<br />
Looking at the structures below, it is apparent that these three enzymes have similar folds. This conservation of tertiary structure is due to extensive similarities at the level of primary amino acid sequence. However, there are small differences in amino acid sequence among the proteins, which are reflected in their different specificities. Each protein cleaves the peptide backbone after (or on the carbonyl side) of a specific type of sidechain. After examining the molecular basis for these functional similarities and differences, you will hopefully see why serine proteases are a classic example of how '''''structure dictates function'''''!<br />
<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/2'>Chymotrypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/4'>Trypsin</scene> <br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/3'>Elastase</scene> <br />
<br />
== '''Active Sites''' ==<br />
Serine proteases perform their catalytic roles using three key residues, which are commonly referred to as the '''catalytic triad''': <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/7'>chymotrypsin catalytic triad</scene>. The elements are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.<br />
* Mouse over or click on the structure to determine the residue numbers for the catalytic residues. (The residue code will appear near the mouse pointer or in the lower left-hand corner of the browser window.) <br />
* You can adjust the zoom in each image by holding down the shift key while you click and drag on the structure. Alternatively, you can click on the Jmol symbol in the lower right-hand corner of each image and select a different zoom percentage from the main menu.<br />
This arrangement of amino acids is also called a '''charge relay system''' <ref>PMID: 7016210</ref>. <br />
<br />
Now compare the active site residues of chymotrypsin to the <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/10'>trypsin catalytic triad</scene> and the <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/8'>elastase catalytic triad</scene>.<br />
<br />
== '''Substrate Binding Pockets''' ==<br />
The next links examine the binding pockets of each protein. The spacefilled residues have been color coded according to hydrophobicity (residues are indicated as: {{Template:ColorKey_Hydrophobic}} or {{Template:ColorKey_Polar}}, with <font color="FF0000">'''Aspartate'''</font> highlighted further ).<br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/4'>chymotrypsin binding pocket</scene>. This structure shows the binding pocket using <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/6'>p-sulfinotoluene</scene>, a bound inhibitor. <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/6'>trypsin binding pocket</scene> contains <font color="FF0000">Asp189</font>. Consider the peptide-based inhibitor called <scene name='User:Amy_Kerzmann/Sandbox_5/New_trypsin-wt-triad/9'>aeruginosin 98-B</scene>, which is now shown in balls and sticks, which residue of this inhibitor is interacting with Asp189? <br />
<br />
*The <scene name='User:Amy_Kerzmann/Sandbox_5/New_elastase-triad/6'>elastase binding pocket</scene>.<br />
== '''Understanding the Mechanism''' ==<br />
==== '''Catalytic Mechanism''' ====<br />
[http://www.whfreeman.com/newcatalog.aspx?search=Lehninger&isbn=071677108X Lehninger's Principles of Biochemistry (5th edition)] describes the catalytic mechanism of chymotrypsin on pages 208-209. An [http://bcs.whfreeman.com/lehninger5e/pages/bcs-main.asp?v=&s=06000&n=00010&i=06010.01&o=|00610|00580|00590|00510|00540|00600|00550|00570|00630|00010|00020|00030|00040|00070|00080|00090|00100|01000|02000|03000|04000|05000|06000|07000|08000|09000|10000|11000|12000|13000|14000|15000|16000|17000|18000|19000|20000|21000|22000|23000|24000|25000|26000|27000|28000|99000| animated version] of the enzyme-catalyzed hydrolysis reaction is also available on the textbook's website. <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'><br />
<br />
This representation</scene> was designed to match the perspective given by those resources. To provide better orientation after this rotation, here are the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/11'>binding pocket residues</scene> that were highlighted above. (Or you can <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/16'>label the catalytic triad and Gly193</scene>.)<br />
<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/12'>show p-sulfinotoluene binding</scene><br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/13'>show just p-sulfinotoluene</scene> (<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/14'>as sticks</scene>) Note that the <scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/15'>sulfino group</scene> would be in approximately the same location as the carbonyl group of the substrate peptide.<br />
*<scene name='User:Amy_Kerzmann/Sandbox_5/New_chymotrypsin-triad/10'>hide binding pocket</scene><br />
<br />
== '''Additional PDB Structures''' ==<br />
In order to easily compare the proteins shown on this page, some portions of the crystal structures have been masked. Although each of these serine proteases functions as a monomer, they are often observed as dimers or even tetramers in crystal structures. These higher-order multimers are not the physiological state of the serine protease, but rather a consequence of the experimental method, which requires high protein concentrations. However, some proteins are only functional in the tetrameric state, such as [http://www.pdb.org/pdb/explore/explore.do?structureId=1GZX hemoglobin]. Therefore, it is important to recognize that one cannot necessarily determine the physiological state from a crystal structure alone.<br />
<br />
To view the full, unmodified structures in the [http://www.pdb.org/pdb/home/home.do RSCB Protein Data Bank], here are links to each of the crystal structures shown above: [http://www.pdb.org/pdb/explore/explore.do?structureId=2cha chymotrypsin (2cha)], [http://www.pdb.org/pdb/explore/explore.do?structureId=1aq7 trypsin (1aq7)] and [http://www.pdb.org/pdb/explore/explore.do?structureId=4est elastase (4est)]. Keep in mind that these are only representative structures of each serine protease. Other structures can be found at the following links:<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=7GCH chymotrypsin (7gch)] This structure is shown in Figure 6-18 (page 206) of [http://www.whfreeman.com/newcatalog.aspx?search=Lehninger&isbn=071677108X Lehninger's Principles of Biochemistry (5th edition)].<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=1acb chymotrypsin (1acb)] This structure includes a bound protein, showing how the peptide fits into the active site of the enzyme.<br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=2cmy trypsin (2cmy)] <br />
* [http://www.pdb.org/pdb/explore/explore.do?structureId=3est elastase (3est)] <br />
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==3D structures of chymotrypsin==<br />
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[[Chymotrypsin]]<br />
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==3D structures of trypsin==<br />
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[[Trypsin]]<br />
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==3D structures of elastase==<br />
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[[Elastase]]<br />
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==References==<br />
<references /></div>Avril Robertson