title: Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.
abstract: 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.
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fleming
authors.forename: Carol C
authors.initials: CC
authors.lastname: Edwards
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Kirby
authors.forename: Donald M
authors.initials: DM
authors.lastname: Maxwell
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cerasoli
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
mesh_terms: D043182:Carboxylesterase / Q000737:chemistry*; D002619:Chemical Warfare Agents / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry*; D012999:Soman / Q000737:chemistry*
chemical_list: D002619:Chemical Warfare Agents; D010755:Organophosphates; D012999:Soman; D043182:Carboxylesterase; C009374:tabun