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PDBsum entry 2hrq
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References listed in PDB file
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Key reference
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Title
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Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
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Authors
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C.D.Fleming,
C.C.Edwards,
S.D.Kirby,
D.M.Maxwell,
P.M.Potter,
D.M.Cerasoli,
M.R.Redinbo.
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Ref.
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Biochemistry, 2007,
46,
5063-5071.
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PubMed id
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Abstract
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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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