2HRQ: Crystal Structure Of Human Liver Carboxylesterase 1 (hce1) In Covalent Complex With The Nerve Agent Soman (gd)

Citation:
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.
PDB ID: 2HRQDownload
MMDB ID: 45474
PDB Deposition Date: 2006/7/20
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Similar Structures:
Biological Unit for 2HRQ: trimeric; determined by author and by software (PISA)
Molecular Components in 2HRQ
Label Count Molecule
Proteins (3 molecules)
3
Liver Carboxylesterase 1
Molecule annotation
Chemicals (18 molecules)
1
3
2
3
3
3
4
6
5
3
* Click molecule labels to explore molecular sequence information.

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