2wu4: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2wu4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WU4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WU4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[2wu4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WU4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WU4 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HBP:1,7-HEPTYLENE-BIS-N,N-SYN-2-PYRIDINIUMALDOXIME'>HBP</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HBP:1,7-HEPTYLENE-BIS-N,N-SYN-2-PYRIDINIUMALDOXIME'>HBP</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SXE:O-{(S)-ETHOXY[(1-METHYLETHYL)AMINO]PHOSPHORYL}-L-SERINE'>SXE</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SXE:O-{(S)-ETHOXY[(1-METHYLETHYL)AMINO]PHOSPHORYL}-L-SERINE'>SXE</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jgh|2jgh]], [[2whq|2whq]], [[1mah|1mah]], [[2ha6|2ha6]], [[1maa|1maa]], [[2c0q|2c0q]], [[2jgg|2jgg]], [[2jgl|2jgl]], [[1q84|1q84]], [[2jgm|2jgm]], [[2jge|2jge]], [[1q83|1q83]], [[2wls|2wls]], [[1c2b|1c2b]], [[2ha3|2ha3]], [[2ha0|2ha0]], [[2jey|2jey]], [[2jgi|2jgi]], [[1n5r|1n5r]], [[2jgj|2jgj]], [[1j06|1j06]], [[2jf0|2jf0]], [[2c0p|2c0p]], [[2h9y|2h9y]], [[2whr|2whr]], [[1n5m|1n5m]], [[2ha5|2ha5]], [[2ha2|2ha2]], [[2whp|2whp]], [[2jez|2jez]], [[2jgk|2jgk]], [[1ku6|1ku6]], [[2ha4|2ha4]], [[1j07|1j07]], [[2jgf|2jgf]], [[2ha7|2ha7]], [[1c2o|1c2o]], [[2wu3|2wu3]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jgh|2jgh]], [[2whq|2whq]], [[1mah|1mah]], [[2ha6|2ha6]], [[1maa|1maa]], [[2c0q|2c0q]], [[2jgg|2jgg]], [[2jgl|2jgl]], [[1q84|1q84]], [[2jgm|2jgm]], [[2jge|2jge]], [[1q83|1q83]], [[2wls|2wls]], [[1c2b|1c2b]], [[2ha3|2ha3]], [[2ha0|2ha0]], [[2jey|2jey]], [[2jgi|2jgi]], [[1n5r|1n5r]], [[2jgj|2jgj]], [[1j06|1j06]], [[2jf0|2jf0]], [[2c0p|2c0p]], [[2h9y|2h9y]], [[2whr|2whr]], [[1n5m|1n5m]], [[2ha5|2ha5]], [[2ha2|2ha2]], [[2whp|2whp]], [[2jez|2jez]], [[2jgk|2jgk]], [[1ku6|1ku6]], [[2ha4|2ha4]], [[1j07|1j07]], [[2jgf|2jgf]], [[2ha7|2ha7]], [[1c2o|1c2o]], [[2wu3|2wu3]]</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wu4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wu4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wu4 RCSB], [http://www.ebi.ac.uk/pdbsum/2wu4 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wu4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wu4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wu4 RCSB], [http://www.ebi.ac.uk/pdbsum/2wu4 PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACES_MOUSE ACES_MOUSE]] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Acetylcholinesterase]] | [[Category: Acetylcholinesterase]] | ||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Artursson, E | [[Category: Artursson, E]] | ||
[[Category: Ekstrom, F | [[Category: Ekstrom, F]] | ||
[[Category: Hornberg, A | [[Category: Hornberg, A]] | ||
[[Category: Pang, Y P | [[Category: Pang, Y P]] | ||
[[Category: Warme, R | [[Category: Warme, R]] | ||
[[Category: Fenamipho]] | [[Category: Fenamipho]] | ||
[[Category: Glycoprotein]] | [[Category: Glycoprotein]] | ||
Revision as of 01:49, 26 December 2014
CRYSTAL STRUCTURE OF MOUSE ACETYLCHOLINESTERASE IN COMPLEX WITH FENAMIPHOS AND ORTHO-7CRYSTAL STRUCTURE OF MOUSE ACETYLCHOLINESTERASE IN COMPLEX WITH FENAMIPHOS AND ORTHO-7
Structural highlights
Function[ACES_MOUSE] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedOrganophosphorus insecticides and nerve agents inhibit the vital enzyme acetylcholinesterase by covalently bonding to the catalytic serine residue of the enzyme. Oxime-based reactivators, such as [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]me thyl]-oxoazanium dichloride (HI-6) and 1,7-heptylene-bis-N,N'-2-pyridiniumaldoxime dichloride (Ortho-7), restore the organophosphate-inhibited enzymatic activity by cleaving the phosphorous conjugate. In this article, we report the intermolecular interactions between Mus musculus acetylcholinesterase inhibited by the insecticide fenamiphos (fep-mAChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and kinetics. The crystal structures of the two oxime-bound fep-mAChE complexes show that both oximes interact with the peripheral anionic site involving different conformations of Trp286 and different peripheral-site residues (Tyr124 for HI-6 and Tyr72 for Ortho-7). Moreover, residues at catalytic site of the HI-6-bound fep-mAChE complex adopt conformations that are similar to those in the apo mAChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-mAChE complex. Interestingly, flipping of the His447 imidazole ring allows the formation of a hydrogen bonding network among the Glu334-His447-Ortho-7 triad, which presumably deprotonates the Ortho-7 oxime hydroxyl group, increases the nucleophilicity of the oxime group, and leads to cleavage of the phosphorous conjugate. These results offer insights into a detailed reactivation mechanism for the oximes and development of improved reactivators. Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad.,Hornberg A, Artursson E, Warme R, Pang YP, Ekstrom F Biochem Pharmacol. 2010 Feb 1;79(3):507-15. Epub 2009 Sep 2. PMID:19732756[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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