2HRR
Crystal structure of Human Liver Carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Tabun (GA)
Summary for 2HRR
| Entry DOI | 10.2210/pdb2hrr/pdb |
| Related PRD ID | PRD_900003 |
| Descriptor | Liver carboxylesterase 1, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, R-ETHYL N,N-DIMETHYLPHOSPHONAMIDATE, ... (7 entities in total) |
| Functional Keywords | hydrolase, carboxylesterase, tabun |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 179526.67 |
| Authors | Fleming, C.D.,Redinbo, M.R. (deposition date: 2006-07-20, release date: 2007-05-01, Last modification date: 2023-08-30) |
| Primary citation | Fleming, C.D.,Edwards, C.C.,Kirby, S.D.,Maxwell, D.M.,Potter, P.M.,Cerasoli, D.M.,Redinbo, M.R. Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun. Biochemistry, 46:5063-5071, 2007 Cited by PubMed 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. PubMed: 17407327DOI: 10.1021/bi700246n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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