2hrq

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Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Soman (GD)

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 104-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.

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):5063-5071. Epub 2007 Apr 4. PMID:17407327

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