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==='''Background Information'''===
==='''Background Information'''===
{|align='right'
 
|[[Image:AChE-Page-Cholinergic-Synapse.jpg|thumb|alt= Alt text| Cholernergic Synapse |375px]]
 
|[[Image:AChE-Page-ACh_shematic.JPG|thumb|alt= Alt text| Chemical Structure of Acetylcholine |300px]]
 
|}
[[Image:AChE-Page-Cholinergic-Synapse.jpg|thumb|alt= Alt text| Figure 2. Cholernergic Synapse |375px]]
 
 
When a nerve impulse reaches the presynaptic nerve terminal, where it stimulates the release of the neurotransmitter, ACh, into the cholinergic synapse. ACh diffuses across the synapse to the postsynaptic nerve terminal, and binds to receptors embedded in the membrane of the  postsynaptic nerve terminal. The binding of ACh to receptors in the postsynaptic neuron re-initiates the nerve impulse. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal, hydrolyzes ACh to acetate and choline resulting in the termination of the nerve  impulse at the synapse.  
When a nerve impulse reaches the presynaptic nerve terminal, where it stimulates the release of the neurotransmitter, ACh, into the cholinergic synapse. ACh diffuses across the synapse to the postsynaptic nerve terminal, and binds to receptors embedded in the membrane of the  postsynaptic nerve terminal. The binding of ACh to receptors in the postsynaptic neuron re-initiates the nerve impulse. Finally AChE, anchored to the membrane of the postsynaptic nerve terminal, hydrolyzes ACh to acetate and choline resulting in the termination of the nerve  impulse at the synapse.  
[[Image:AChE-Page-ACh_shematic.JPG|left|thumb|alt= Alt text| Figure 1. Chemical Structure of Acetylcholine |275px]]
Inhibition of AChE may result in different outcomes, depending on the physiological context. Toxins such as FAS-II from the East African Green Mamba snake inhibit AChE and ultimately lead to death. Conversely, reversible inhibition of AChE, in patients with Alzheimer’s disease, is an effective way to improve their symptoms, including memory loss and disorientation.


Inhibition of AChE may result in different outcomes, depending on the physiological context. Toxins such as FAS-II from the East African Green Mamba snake inhibit AChE and ultimately lead to death. Conversely, reversible inhibition of AChE, in patients with Alzheimer’s disease, is an effective way to improve their symptoms, including memory loss and disorientation.
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Reflected in our design are two key concepts of AChE biology: the mechanism by which AChE hydrolyses ACh (the substrate traffic story), and how the Green Mamba Snake toxin, FAS-II, inhibits the hydrolysis of ACh (the inhibition story). Two physical models were designed and fabricated using a combination of computational molecular modeling and 3D printing technology: ''Tc''AChE in complex with a modeled ACh ligand, and ''Tc''AChE in complex with FAS-II. Both models were designed using the respective protein data bank (PDB) files: 2ace for the ''Tc''AChE/ACh complex and 1fss for the''Tc''AChE/FAS-II complex, and RasMol computer modeling program.  
Reflected in our design are two key concepts of AChE biology: the mechanism by which AChE hydrolyses ACh (the substrate traffic story), and how the Green Mamba Snake toxin, FAS-II, inhibits the hydrolysis of ACh (the inhibition story). Two physical models were designed and fabricated using a combination of computational molecular modeling and 3D printing technology: ''Tc''AChE in complex with a modeled ACh ligand, and ''Tc''AChE in complex with FAS-II. Both models were designed using the respective protein data bank (PDB) files: 2ace for the ''Tc''AChE/ACh complex and 1fss for the''Tc''AChE/FAS-II complex, and RasMol computer modeling program.  


===='''Features of the Substrate Traffic Story:''a Model of'' AChE/ACh'''====


<applet load='2ace' size='500' frame='true' align='left' scene='Sandbox_250/Ache_ach/1' caption='AChE/ACh'/>
[[Image:AChE-Page-schematic-gorge.jpg|thumb|alt= Alt text| Figure 3. Schematic illustration of AChE. |525px]]


<applet load='2ace' size='450' frame='true' align='left' scene='Sandbox_250/Ache_ach/1' caption='AChE/ACh'/>
===='''Features of the Substrate Traffic Story:''a Model of'' AChE/ACh'''====


The ''Tc''<scene name='Sandbox_250/Ache_ach/5'>AChE</scene> protein contains 537 amino acids and forms an α/β hydrolase fold. The neurotransmitter <scene name='Sandbox_250/Ache_ach/35'>ACh</scene> consists of an acytoxy group, an ethylene group and a positively charged quaternary ammonium ion.
The ''Tc''<scene name='Sandbox_250/Ache_ach/5'>AChE</scene> protein contains 537 amino acids and forms an α/β hydrolase fold. The neurotransmitter <scene name='Sandbox_250/Ache_ach/35'>ACh</scene> consists of an acytoxy group, an ethylene group and a positively charged quaternary ammonium ion.
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The AChE active site includes three residues that form a catalytic triad: <scene name='Sandbox_250/Ache_ach/20'>Ser200, Glu327, and His440</scene>. The <scene name='Sandbox_250/Ache_ach/33'>Catalytic Triad</scene>, highlighted in blue, is responsible for the hydrolysis of ACh into acetate and choline.
The AChE active site includes three residues that form a catalytic triad: <scene name='Sandbox_250/Ache_ach/20'>Ser200, Glu327, and His440</scene>. The <scene name='Sandbox_250/Ache_ach/33'>Catalytic Triad</scene>, highlighted in blue, is responsible for the hydrolysis of ACh into acetate and choline.


[[Image:AChE-Page-schematic-gorge.jpg|thumb|alt= Alt text| Schematic illustration of AChE. |500px]]




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===='''Features of the Inhibition Story: a Model of AChE/FAS-II'''====


 
<applet load='1fss' size='500' frame='true' align='right' scene='Sandbox_250/Ache_fas2/6' caption='AChE/FAS-II' />
 
 
<applet load='1fss' size='450' frame='true' align='right' scene='Sandbox_250/Ache_fas2/6' caption='AChE/FAS-II' />
 
===='''Features of the Inhibition Story: a Model of AChE/FAS-II'''====


The Green Mamba snake toxin, <scene name='Sandbox_250/Ache_fas2/9'>FAS-II</scene>, is a 61-residue protein that folds into 4β sheets, with 3 of the 4β sheets forming loops, or fingers.   
The Green Mamba snake toxin, <scene name='Sandbox_250/Ache_fas2/9'>FAS-II</scene>, is a 61-residue protein that folds into 4β sheets, with 3 of the 4β sheets forming loops, or fingers.   
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3. Shape: Once bound to the PAS, two loops of FAS-II fit in to the AChE active-site gorge like a hand fits into a glove. Once this occurs, the entrance of the gorge is <scene name='Sandbox_250/Ache_fas2/13'>blocked</scene> such that acetylcholine may not enter, and therefore it will not be hydrolysed. This results in the increased levels of AChE in the cholinergic synapse, and ultimately death.
3. Shape: Once bound to the PAS, two loops of FAS-II fit in to the AChE active-site gorge like a hand fits into a glove. Once this occurs, the entrance of the gorge is <scene name='Sandbox_250/Ache_fas2/13'>blocked</scene> such that acetylcholine may not enter, and therefore it will not be hydrolysed. This results in the increased levels of AChE in the cholinergic synapse, and ultimately death.


[[Image:AChE-Page-schematic-fas.JPG|left|thumb|alt= Alt text| Schematic illustration of the AChE/FAS-II complex. |500px]]
[[Image:AChE-Page-schematic-fas.JPG|left|thumb|alt= Alt text| Figure 4. Schematic illustration of the AChE/FAS-II complex. |500px]]


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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Joel L. Sussman, Allison Granberry, Jaime Prilusky
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