2hrq
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The organophosphorus nerve agents sarin, soman, tabun, and VX exert their | + | The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure. |
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| + | ==Disease== | ||
| + | Known disease associated with this structure: Monocyte carboxylesterase deficiency (1) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114835 114835]] | ||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
| - | Crystal | + | Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun., Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR, Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17407327 17407327] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fleming, C | + | [[Category: Fleming, C D.]] |
| - | [[Category: Redinbo, M | + | [[Category: Redinbo, M R.]] |
[[Category: GD7]] | [[Category: GD7]] | ||
[[Category: NAG]] | [[Category: NAG]] | ||
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[[Category: soman]] | [[Category: soman]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:45:03 2008'' |
Revision as of 15:45, 21 February 2008
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Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Soman (GD)
Contents |
Overview
The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.
Disease
Known disease associated with this structure: Monocyte carboxylesterase deficiency (1) OMIM:[114835]
About this Structure
2HRQ is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Hydrolase, with EC number 3.1.1.1. Full crystallographic information is available from OCA.
Reference
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun., Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR, Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:17407327
Page seeded by OCA on Thu Feb 21 17:45:03 2008
Categories: Homo sapiens | Hydrolase | Single protein | Fleming, C D. | Redinbo, M R. | GD7 | NAG | SIA | SO4 | SUC | Carboxylesterase | Soman
