1xlw
From Proteopedia
(New page: 200px<br /> <applet load="1xlw" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xlw, resolution 2.10Å" /> '''Diethylphosphorylat...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1xlw.gif|left|200px]]<br /> | + | [[Image:1xlw.gif|left|200px]]<br /><applet load="1xlw" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xlw" size=" | + | |
caption="1xlw, resolution 2.10Å" /> | caption="1xlw, resolution 2.10Å" /> | ||
'''Diethylphosphorylated Butyrylcholinesterase (Nonaged) Obtained By Reaction With Echothiophate'''<br /> | '''Diethylphosphorylated Butyrylcholinesterase (Nonaged) Obtained By Reaction With Echothiophate'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Organophosphorus poisons (OP) bind covalently to the active-site serine of | + | Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1XLW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG, SO4, CL, DEP, S and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1XLW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=DEP:'>DEP</scene>, <scene name='pdbligand=S:'>S</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XLW OCA]. |
==Reference== | ==Reference== | ||
| Line 18: | Line 17: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Asojo, O | + | [[Category: Asojo, O A.]] |
| - | [[Category: Borgstahl, G | + | [[Category: Borgstahl, G E.O.]] |
[[Category: Lockridge, O.]] | [[Category: Lockridge, O.]] | ||
[[Category: Masson, P.]] | [[Category: Masson, P.]] | ||
| Line 31: | Line 30: | ||
[[Category: cholinesterase; bche]] | [[Category: cholinesterase; bche]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:56:11 2008'' |
Revision as of 13:56, 21 February 2008
|
Diethylphosphorylated Butyrylcholinesterase (Nonaged) Obtained By Reaction With Echothiophate
Contents |
Overview
Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.
Disease
Known diseases associated with this structure: Apnea, postanesthetic OMIM:[177400]
About this Structure
1XLW is a Single protein structure of sequence from Homo sapiens with , , , , and as ligands. Active as Cholinesterase, with EC number 3.1.1.8 Full crystallographic information is available from OCA.
Reference
Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging., Nachon F, Asojo OA, Borgstahl GE, Masson P, Lockridge O, Biochemistry. 2005 Feb 1;44(4):1154-62. PMID:15667209
Page seeded by OCA on Thu Feb 21 15:56:11 2008
Categories: Cholinesterase | Homo sapiens | Single protein | Asojo, O A. | Borgstahl, G E.O. | Lockridge, O. | Masson, P. | Nachon, F. | CL | DEP | GOL | NAG | S | SO4 | Cholinesterase; bche
