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| | ==Crystal structure of soman-aged human butyrylcholinesterase in complex with benzyl pyridinium-4-methyltrichloroacetimidate== | | ==Crystal structure of soman-aged human butyrylcholinesterase in complex with benzyl pyridinium-4-methyltrichloroacetimidate== |
| - | <StructureSection load='4b0o' size='340' side='right' caption='[[4b0o]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='4b0o' size='340' side='right'caption='[[4b0o]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4b0o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B0O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B0O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4b0o]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B0O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B0O FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=15F:1-BENZYL-4-({[(1E)-2,2,2-TRICHLOROETHANIMIDOYL]OXY}METHYL)PYRIDINIUM'>15F</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SBG:O-[(S)-HYDROXY(METHYL)PHOSPHORYL]-L-SERINE'>SBG</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=15F:1-BENZYL-4-({[(1E)-2,2,2-TRICHLOROETHANIMIDOYL]OXY}METHYL)PYRIDINIUM'>15F</scene>, <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SBG:O-[(S)-HYDROXY(METHYL)PHOSPHORYL]-L-SERINE'>SBG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1eho|1eho]], [[1ehq|1ehq]], [[1kcj|1kcj]], [[1p0i|1p0i]], [[1p0m|1p0m]], [[1p0p|1p0p]], [[1p0q|1p0q]], [[1xlu|1xlu]], [[1xlv|1xlv]], [[1xlw|1xlw]], [[2j4c|2j4c]], [[2wid|2wid]], [[2wif|2wif]], [[2wig|2wig]], [[2wij|2wij]], [[2wik|2wik]], [[2wil|2wil]], [[2wsl|2wsl]], [[2xmb|2xmb]], [[2xmc|2xmc]], [[2xmd|2xmd]], [[2xmg|2xmg]], [[2xqf|2xqf]], [[2xqg|2xqg]], [[2xqi|2xqi]], [[2xqj|2xqj]], [[2xqk|2xqk]], [[2y1k|2y1k]], [[4aqd|4aqd]], [[4axb|4axb]], [[4b0p|4b0p]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b0o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b0o OCA], [https://pdbe.org/4b0o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b0o RCSB], [https://www.ebi.ac.uk/pdbsum/4b0o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b0o ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cholinesterase Cholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.8 3.1.1.8] </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=4b0o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b0o OCA], [http://pdbe.org/4b0o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b0o RCSB], [http://www.ebi.ac.uk/pdbsum/4b0o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b0o ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN]] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[http://omim.org/entry/177400 177400]]. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. | + | [https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:[https://omim.org/entry/177400 177400]. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN]] Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.<ref>PMID:19542320</ref> <ref>PMID:19452557</ref> | + | [https://www.uniprot.org/uniprot/CHLE_HUMAN CHLE_HUMAN] Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.<ref>PMID:19542320</ref> <ref>PMID:19452557</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Butyrylcholinesterase|Butyrylcholinesterase]] | + | *[[Butyrylcholinesterase 3D structures|Butyrylcholinesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cholinesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Goeldner, M]] | + | [[Category: Goeldner M]] |
| - | [[Category: Grol, M van]]
| + | [[Category: Nachon F]] |
| - | [[Category: Koning, M de]]
| + | [[Category: Noort D]] |
| - | [[Category: Nachon, F]] | + | [[Category: Wandhammer M]] |
| - | [[Category: Noort, D]] | + | [[Category: De Koning M]] |
| - | [[Category: Wandhammer, M]] | + | [[Category: Van Grol M]] |
| - | [[Category: Aging]] | + | |
| - | [[Category: Hydrolase]] | + | |
| Structural highlights
4b0o is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.35Å |
| Ligands: | , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
CHLE_HUMAN Defects in BCHE are the cause of butyrylcholinesterase deficiency (BChE deficiency) [MIM:177400. BChE deficiency is a metabolic disorder characterized by prolonged apnoea after the use of certain anesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency. BChE deficiency is a multifactorial disorder. The hereditary condition is transmitted as an autosomal recessive trait.
Function
CHLE_HUMAN Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.[1] [2]
Publication Abstract from PubMed
Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase.
A step toward the reactivation of aged cholinesterases - Crystal structure of ligands binding to aged human butyrylcholinesterase.,Wandhammer M, de Koning M, van Grol M, Loiodice M, Saurel L, Noort D, Goeldner M, Nachon F Chem Biol Interact. 2012 Aug 16. PMID:22922115[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chilukuri N, Duysen EG, Parikh K, diTargiani R, Doctor BP, Lockridge O, Saxena A. Adenovirus-transduced human butyrylcholinesterase in mouse blood functions as a bioscavenger of chemical warfare nerve agents. Mol Pharmacol. 2009 Sep;76(3):612-7. doi: 10.1124/mol.109.055665. Epub 2009 Jun, 19. PMID:19542320 doi:10.1124/mol.109.055665
- ↑ Amitay M, Shurki A. The structure of G117H mutant of butyrylcholinesterase: nerve agents scavenger. Proteins. 2009 Nov 1;77(2):370-7. doi: 10.1002/prot.22442. PMID:19452557 doi:10.1002/prot.22442
- ↑ Wandhammer M, de Koning M, van Grol M, Loiodice M, Saurel L, Noort D, Goeldner M, Nachon F. A step toward the reactivation of aged cholinesterases - Crystal structure of ligands binding to aged human butyrylcholinesterase. Chem Biol Interact. 2012 Aug 16. PMID:22922115 doi:10.1016/j.cbi.2012.08.005
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