Sandbox 250: Difference between revisions
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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. | ||
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<applet load='2ace' size='300' frame='true' align='left' scene='Sandbox_250/Ache_ach/1' caption='AChE/ACh'/> | <applet load='2ace' size='300' frame='true' align='left' scene='Sandbox_250/Ache_ach/1' caption='AChE/ACh'/> | ||
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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>, highlithed 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>, highlithed in blue, is responsible for the hydrolysis of ACh into acetate and choline. | ||
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<applet load='1fss' size='300' frame='true' align='right' scene='Sandbox_250/Ache_fas2/6' caption='AChE/FAS-II' /> | <applet load='1fss' size='300' frame='true' align='right' scene='Sandbox_250/Ache_fas2/6' caption='AChE/FAS-II' /> | ||
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===='''Features of the Inhibition Story: a Model of 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 | 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. | ||
FAS-II binds to and inhibits AChE using two major mechanisms: | FAS-II binds to and inhibits AChE using two major mechanisms: | ||
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2. 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. | 2. 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. | ||