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Flexibility of aromatic residues in acetylcholinesterase: Difference between revisions

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<applet load='1ea5.pdb' size='350' frame='true' scene='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Ache_apo_14aromaticresidues/1' align='right' caption="3D structure of TcAChE based on pdb code 1ea5" />
<applet load='1ea5.pdb' size='350' frame='true' scene='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Ache_apo_14aromaticresidues/2' align='right' caption="3D structure of TcAChE based on pdb code 1ea5" />




== Flexibility of aromatic residues in the active-gorge of AChE ==
== Flexibility of aromatic residues in the active-gorge of AChE ==
The high aromatic content of the deep and narrow active-site gorge of acetylcholinesterase (AChE) is a remarkable feature of this enzyme.There are <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/14_residues/6'>14 conserved aromatic amino acids</scene> lined along the gorge of ''Torpedo californica'' AChE (TcAChE), F120, F288, F290, F330, F331, W84, W233, W279, W432, Y70, Y121, Y130, Y334, and Y442. The side-chain conformational analyses based on the multuple available crystal structures and molecular dyanmics (MD) simulation trajectories show that the degree of flexibility of these 14 aromatic side chains is diverse. While those of <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/W279_f330/2'>F330 and W279 </scene>are both very flexible, the side-chain conformations of <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Groupii/2'>F120, W233, W432, Y70, Y121, F288, F290 and F331</scene> appear to be fixed. Residues located on, or adjacent to the <scene name='Aromatic_residues/14_residues_omegaloop/1'>omega-loop (C67-C94)</scene>, viz. <scene name='Aromatic_residues/14_residues_group3/2'>W84, Y130, Y442, and Y334</scene>, display different flexibilities in the MD simulations and in the crystal structures.
The high aromatic content of the deep and narrow active-site gorge of '''acetylcholinesterase''' (AChE) is a remarkable feature of this enzyme.There are <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/14_residues/11'>14 conserved aromatic amino acids</scene> lined along the gorge of ''Torpedo californica'' AChE (TcAChE), F120, F288, F290, F330, F331, W84, W233, W279, W432, Y70, Y121, Y130, Y334, and Y442. The side-chain conformational analyses based on the multuple available crystal structures and molecular dyanmics (MD) simulation trajectories show that the degree of flexibility of these 14 aromatic side chains is diverse. While those of <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/W279_f330/3'>F330 and W279 </scene>are both very flexible, the side-chain conformations of <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Groupii/4'>F120, W233, W432, Y70, Y121, F288, F290 and F331</scene> appear to be fixed. Residues located on, or adjacent to the <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Omega_loop/3'>omega-loop (C67-C94)</scene>, viz. <scene name='Flexibility_of_aromatic_residues_in_acetylcholinesterase/Groupiii/6'>W84, Y130, Y442, and Y334</scene>, display different flexibilities in the MD simulations and in the crystal structures.


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=== Group II: residues with flexible side chains ===
=== Group II: residues with flexible side chains ===
[[Image:W279_3_low.jpg|thumb|Fig. 2. The &#967;<sub>1</sub>/&#967;<sub>2</sub> plots of W279. Details in the plots are as in Fig. 1 except that the grey areas in the right plot are the favorable regions for the side-chain of Trp predicted by PROCHECK. |450px|right]]
[[Image:W279_3_low.jpg|thumb|Fig. 2. The &#967;<sub>1</sub>/&#967;<sub>2</sub> plots of W279. Details in the plots are as in Fig. 1 except that the grey areas in the right plot are the favorable regions for the side-chain of Trp predicted by PROCHECK. |450px|right]]
<applet load=Pp_W279_abcde_m3.pdb' size='320' frame='true' scene='Flexibility_of_aromatic_residues_in_acetylcholinesterase/W279_animation3/1' align='left' caption="This is an animation to show the 7 conformations of W279 according to the 7 groups, a, b, c, d, e, f, and g, shown in Fig. 2. The side-chain of W279 is colored in red and the ligands in green." />
<applet size='320' frame='true' scene='Flexibility_of_aromatic_residues_in_acetylcholinesterase/W279_animation3/1' align='left' caption="This is an animation to show the 7 conformations of W279 according to the 7 groups, a, b, c, d, e, f, and g, shown in Fig. 2. The side-chain of W279 is colored in red and the ligands in green." />




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===Additional Resources===
For additional information, see: [[Alzheimer's Disease]]
<br />


== References ==
== References ==


*[http://www.proteinscience.org/cgi/content/abstract/17/4/601] Yechun Xu, Jacques Philippe Colletier, Hualiang Jiang, Israel Silman, Joel L. Sussman, Martin Weik. Induced-fit of preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design. Prot. Sci. 2008, 17, 601-605.  
*[http://www.proteinscience.org/cgi/content/abstract/17/4/601] Yechun Xu, Jacques Philippe Colletier, Hualiang Jiang, Israel Silman, Joel L. Sussman, Martin Weik. Induced-fit of preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design. Prot. Sci. 2008, 17, 601-605.  
*[http://www.biophysj.org/cgi/content/abstract/biophysj.108.129601v1] Yechun Xu, Jacques Philippe Colletier, Martin Weik, Hualiang Jiang, John Moult, Israel Silman, Joel L. Sussman. Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray vs MD. Biophys. J. (in press).
*[http://www.biophysj.org/cgi/content/abstract/biophysj.108.129601v1] Yechun Xu, Jacques Philippe Colletier, Martin Weik, Hualiang Jiang, John Moult, Israel Silman, Joel L. Sussman. Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray vs MD. Biophys. J. 2008, 95, 2500-2511.
Ache_apo_14aromaticresidues
Ache_apo_14aromaticresidues

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Yechun Xu, Eran Hodis, Joel L. Sussman, David Canner, Michal Harel
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