Ekstrom_2006_Biochemistry_45_74

Reference

Title : Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase - Ekstrom_2006_Biochemistry_45_74
Author(s) : Ekstrom F , Akfur C , Tunemalm AK , Lundberg S
Ref : Biochemistry , 45 :74 , 2006
Abstract : Organophosphorus compounds (OPs) interfere with the catalytic mechanism of acetylcholinesterase (AChE) by rapidly phosphorylating the catalytic serine residue. The inhibited enzyme can at least partly be reactivated with nucleophilic reactivators such as oximes. The covalently attached OP conjugate may undergo further intramolecular dealkylation or deamidation reactions, a process termed "aging" that results in an enzyme considered completely resistant to reactivation. Of particular interest is the inhibition and aging reaction of the OP compound tabun since tabun conjugates display an extraordinary resistance toward most reactivators of today. To investigate the structural basis for this resistance, we determined the crystal structures of Mus musculus AChE (mAChE) inhibited by tabun prior to and after the aging reaction. The nonaged tabun conjugate induces a structural change of the side chain of His447 that uncouples the catalytic triad and positions the imidazole ring of His447 in a conformation where it may form a hydrogen bond to a water molecule. Moreover, an unexpected displacement of the side chain of Phe338 narrows the active site gorge. In the crystal structure of the aged tabun conjugate, the side chains of His447 and Phe338 are reversed to the conformation found in the apo structure of mAChE. A hydrogen bond between the imidazole ring of His447 and the ethoxy oxygen of the aged tabun conjugate stabilizes the side chain of His447. The displacement of the side chain of Phe338 into the active site gorge of the nonaged tabun conjugate may interfere with the accessibility of reactivators and thereby contribute to the high resistance of tabun conjugates toward reactivation.
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PubMedSearch : Ekstrom_2006_Biochemistry_45_74
PubMedID: 16388582
Gene_locus related to this paper: mouse-ACHE

Related information

Gene_locus related to this paper: mouse-ACHE

Citations formats

Ekstrom F, Akfur C, Tunemalm AK, Lundberg S (2006)
Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase
Biochemistry 45 :74

Ekstrom F, Akfur C, Tunemalm AK, Lundberg S (2006)
Biochemistry 45 :74