Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-Oxime triad - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemical Pharmacology Année : 2009

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-Oxime triad

Andreas Hörnberg
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Elisabet Artursson
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Rikard Wärme
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Yuan-Ping Pang
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Fredrik Ekström
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Résumé

Organophosphorus insecticides and nerve agents inhibit the vital enzyme acetylcholinesterase by covalently bonding to the catalytic serine residue of the enzyme. Oxime-based reactivators, such as [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) and 1,7-heptylene-bis-,′-2-pyridiniumaldoxime dichloride (Ortho-7), restore the organophosphate-inhibited enzymatic activity by cleaving the phosphorous conjugate. In this article, we report the intermolecular interactions between acetylcholinesterase inhibited by the insecticide fenamiphos (fep-AChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and reactivation kinetics. The crystal structures of the two oxime-bound fep-mAChE complexes show that both oximes interact with the peripheral anionic site involving different conformations of Trp286 and different peripheral-site residues (Tyr124 for HI-6 and Tyr72 for Ortho-7). Moreover, residues at catalytic site of the HI-6-bound fep-AChE complex adopt conformations that are similar to those in the AChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-AChE complex. Interestingly, flipping of the His447 imidazole ring allows the formation of a hydrogen bonding network among the Glu334-His447-Ortho-7 triad, which presumably deprotonates the Ortho-7 oxime hydroxyl group, increases the nucleophilicity of the oxime group, and leads to cleavage of the phosphorous conjugate. These results offer insights into a detailed reactivation mechanism for the oximes and development of improved reactivators.
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hal-00538094 , version 1 (21-11-2010)

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Andreas Hörnberg, Elisabet Artursson, Rikard Wärme, Yuan-Ping Pang, Fredrik Ekström. Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-Oxime triad. Biochemical Pharmacology, 2009, 79 (3), pp.507. ⟨10.1016/j.bcp.2009.08.027⟩. ⟨hal-00538094⟩

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