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| | <!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> | | <!-- INSERT YOUR SCENES AND TEXT BELOW THIS LINE --> |
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| - | =='''Antithrombin III: Devourer of Memories'''== | + | =='''YourMacromolecule'''== |
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| | ===Introduction=== | | ===Introduction=== |
| - | <Structure load='1jvq' size='500' frame='true' align='right' caption='Antithrombin III' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
| - | Slowly losing one's mind is a terrible experience, and it is especially hard on those who have to watch it happen to one of their loved ones. We can all agree that dementia is a disease worth curing: to do that we must first determine its cause.
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| - | The most likely culprit for the cause of some dementias are a group of protease inhibitors called serpins. Serpins are an unusual group as inhibitors go because while most inhibitors simply block the binding site, serpins undergo conformational changes when they bind. Mutations can alter those conformational changes. When this happens, the serpins can no longer function as inhibitors, and instead polymerize to form long chains of worthless protein. These chains eventually grow so long that they destroy the cell and spread into the surrounding tissue, causing further damage and eventually resulting in organ failure. Mutations in the conformational structure of neuroserpin, a serpin found in neurons, has been blamed for the deterioration of brain function seen in dementia.
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| - | <scene name='Sandbox_Reserved_432/1jvq/2'>Dimensions of Dementia</scene> | + | |
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| | ===Overall Structure=== | | ===Overall Structure=== |
| - | <Structure load='1jvq' size='500' frame='true' align='right' caption='Overall Structure' scene='Insert optional scene name here' /> | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, insert caption here' scene='Sandbox_Reserved_430/Intra-strand_phosphate/1' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | Our protein, Antithrombin III is a heterodimer. <ref> Whisstock JC, Pike RN. et al. (2000). "Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin". J. Mol. Biol. 301 (5): 1287–1305. doi:10.1006/jmbi.2000.3982. PMID 10966821.</ref> This <scene name='Sandbox_Reserved_432/Antithrombin_chains/1'>heterodimer</scene> consists of 2 chains, referred to as the L and I chains. The <font color='blue'>I chain</font> is also known as the native form of the protein monomer, while the <font color='yellow'>L chain</font> is also known as the latent form. The native form naturally degrades into the latent form over time, a process that may be sped up by heating, or heating in citrate. <ref>Wardell MR, Chang WS. et al. (1997). "Preparative induction and characterization of L-antithrombin: a structural homologue of latent plasminogen activator inhibitor-1". Biochemistry 36 (42): 13133–13142. doi:10.1021/bi970664u. PMID 9335576. </ref> Fun fact: a pre-latent form has also been isolated and shows some promise as an inhibitor of tumor growth.
| + | ===Binding Interactions=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | We see a great deal of similarity between the <scene name='Sandbox_Reserved_432/Serpin_monomeri/1'>native form</scene> and the <scene name='Sandbox_Reserved_432/Serpin_monomerl/1'>latent form</scene>. Most notably we still see the <font color='red'>(A) β-sheet</font> <scene name='Sandbox_Reserved_432/Antithrombin_sheeta/1'>(shown here)</scene> and the <font color='cyan'>(B) β-sheet</font> <scene name='Sandbox_Reserved_432/Antithrombin_sheetb/1'>(shown here)</scene> in both forms.
| + | ===Additional Features=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
| | + | <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> |
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| - | note:these sheets are shown in the latent form
| + | ===Quiz Question 1=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | The most significant difference between the two forms lies in the reative site loop. In the <font color='orange'>native form</font>, we can see a very nice <scene name='Sandbox_Reserved_432/Antithrombin_nativeloop/1'>reactive loop</scene>, while in the <scene name='Sandbox_Reserved_432/Antithrombin_reactiveloop/1'>latent form</scene> the reactive site loop is not a loop at all.
| + | ===Quiz Question 2=== |
| | + | <Structure load='1a84' size='300' frame='true' align='right' caption='pdbcode, Insert caption here' scene='Insert optional scene name here' /> |
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| - | Also of note is the <font color='cyan'>blocking peptide</font> that is not a part of the protein itself, but has a great deal of significance when it comes to applications and is shown <scene name='Sandbox_Reserved_432/Blocking_peptide1/1'>here</scene>.
| + | ===Credits=== |
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| | + | Introduction - name of team member |
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| | + | Overall Structure - name of team member |
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| | + | Drug Binding Site - name of team member |
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| | + | Additional Features - name of team member |
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| | + | Quiz Question 1 - name of team member |
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| - | | + | Quiz Question 2 - name of team member |
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| - | <font color='white'>spacing</font>
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| - | ===Drug Binding Interactions===
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| - | <Structure load='4caa' size='500' frame='true' align='right' caption='Binding Interactions' scene='Insert optional scene name here' />
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| - | Quite a few forms of dementia arise due to serpins forming long chains with one another. Mutant serine protease inhibitors link their <span style="color:blue">'''reactive site loop'''</span> into the middle strand (s4A) position of the <span style="color:red">'''A ß-sheet'''</span> of another (<scene name='Sandbox_Reserved_432/Antichymotrypsin/3'>Antichymotrypsin</scene>)<ref>Lukacs CM, Zhong JQ, Plotnick MI, Rubin H, Cooperman BS, Christianson DW. Arginine substitutions in the hinge region of antichymotrypsin affect serpin beta-sheet rearrangement. Nat Struct Biol. 1996 Oct;3(10):888-93. PMID:8836107</ref> . They will continue hooking on to one another and create very long polymers.
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| - | Researchers at the University of Cambridge have found a couple of ways in order to negate these linkages, but only one way has been shown to be practical. Binding interactions for polymerisation and blocking polymerisation occur at the antithrombin at the residue locations P14-1. The reason why the serpins form chains with one another is due to their <span style="color:red">'''A sheet'''</span> "opening". This is kept open by random <span style="color:magenta">'''P14-P8/9'''</span> peptides that anneal to the upper half of the s4A position. This allows a domain exchange with the insertion of the P8-3 portion of the loop on another serpin molecule into the lower half of the s4A position (<scene name='Sandbox_Reserved_432/Open_a_sheet/2'>A ß-sheet that is open</scene>). They originally discovered that serpin polymerization could be blocked with synthetic P14-3 or P7-2 peptides. However, in terms of practicality, they were ultimately ineffective; the peptides were far too large for mimetic drug design and many tests proved that the binding of these peptides were far too unpredictable. After conducting crystallographic studies, the synthetic peptides would be found attached to other parts of the serpin.<ref>Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW. How small peptides block and reverse serpin polymerisation. J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247 doi:10.1016/j.jmb.2004.07.078</ref>
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| - | The molecule that was effective was a tetrapeptide called WMDF (Trp-Met-Asp-Phe). Derived from cholecystokinin, this tetrapeptide blocked the polymerisation of antitrypsin and antithrombin. The structure of this peptide was observed at greater detail and the researchers at Cambridge started to test out the effectiveness of other tetra and tripeptides. What they found out is that WMDF binds to the
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| - | P14-8 peptide-antithrombin binary complex. Specifically, it occupies the <span style="color:darkorange">'''P7-P4 vacancy'''</span> and forms 8 hydrogen bonds with the adjacent residues, which prevents another serpin's reactive loop from forming bonds (<scene name='Sandbox_Reserved_432/Binding_site/7'>WMDF Binding Site</scene>). The tetrapeptide's bulky side chains are what contributes to its effectiveness as a blocker of serpin polymerisation. The P4 & P6 locations are very critical; WMDF has methionine at the P6 location and phenylalanine at the P4 location. The hydrophobicity of these regions results in a shift of the connecting loop when compared to latent antithrombin, which results in successful anithrombin polymerisation inhibition. Peptides that were homologous in the P4 & P6 regions to WMDF were also effective (FMRF & FLRF)<ref>Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW. How small peptides block and reverse serpin polymerisation. J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247 doi:10.1016/j.jmb.2004.07.078</ref>
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| - | ===Additional Features===
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| - | <Structure load='1jvq' size='500' frame='true' align='right' caption='Additional Features' scene='Insert optional scene name here' />
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| - | Since Alzheimer's is such a common threat there have been many attempts at finding ways to prevent and cure it. The main goal is to prevent intermolecular linkages from being formed from <scene name='Sandbox_Reserved_432/Beta_sheets_overview/1'>beta sheets</scene>. With this goal in mind they are trying develop therapies to aid in the prevention of these linkages. 10 million Europeans carry what we call the Z allele of antitrypsin.<ref>Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW. How small peptides block and reverse serpin polymerisation. J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247 doi:10.1016/j.jmb.2004.07.078</ref> This doesn't directly mean you are at health risk though. The Z allele gives your body the ability to polymerize and store up to half of their antitrypsin in their liver cells. The problem arises when the formation exceeds the limits of the liver cells which can cause cell death which leads to organ failure.<ref>"Serpin." Wikipedia. Wikimedia Foundation, 25 Apr. 2012. Web. 25 Apr. 2012. <http://en.wikipedia.org/wiki/Serpin>.</ref>
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| - | Therapeutic techniques have been developed to help stop this over-formation of antitrypsin. Instead of trying to just stop the formation of antitrypsin, researchers have found a way on how they can actually change the direction of equilibrium so that it will favor dissociation. This can be achieved by the use of an agent to bind to the unstable protein forms to slowdown and stop the formation.
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| - | At first the only way they would be able to accomplish this binding was with a minimum of 6 amino acids. The problem with this is that the peptides were not going to be small enough. What they found out was that they could block this now by the use of only 3-4 amino acids.<ref>Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW. How small peptides block and reverse serpin polymerisation. J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247 doi:10.1016/j.jmb.2004.07.078</ref> Now these smaller peptides are of more use because now they can be used for oral drug therapy which is the best way to target all the intercellular problems. This means that we could stop the serpin-serpin interactions with each other which originates in the <scene name='Sandbox_Reserved_432/Beta_sheet_gap/1'>beta sheet</scene> at the bottom with the <span style="color:blue">'''open hole'''</span>. This was found out by how <scene name='Sandbox_Reserved_432/Binding_of_glycerol/3'>glycerol</scene> was able to bind to the site (represented by the ball and stick figure) between the two beta strands that are responsible for the polymerisation. This showed that with enough glycerol to bind to these sites that we could effectively prevent the formation of polymers which are essential to our disease.
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| - | ===Credits===
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| - | Introduction - Kevin Dillon
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| - | Overall Structure - Max Nowak
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| - | Drug Binding Site - Kyle Reed
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| - | Additional Features - Chris Carr
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| | ===References=== | | ===References=== |
| | <references/> | | <references/> |
