2gyu

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spinqualitylabelsall models 2gyu, resolution 2.200Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of Mus musculus Acetylcholinesterase in complex with HI-6

Overview

Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds, (OPs) such as pesticides and nerve agents causes acute toxicity or death, of the intoxicated individual. The inhibited AChE may be reactivated by, certain oximes as antidotes for clinical treatment of OP-intoxications., Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex, with Mus musculus acetylcholinesterase (mAChE) reveal different roles of, the peripheral anionic site (PAS) in the binding of the oximes. A limited, structural change of the side chains of Trp286 and Asp74 facilitates the, intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the, side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of, HI-6 is accommodated at the entrance of the catalytic site with the, oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295., In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the, PAS is facilitated by an extended structural change of Trp286 that allows, one of the carboxyimino pyridinium rings to form a cation-pi interaction, with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7, and obidoxime is loosely coordinated in the active-site gorge, whereas the, second carboxyimino pyridinium ring is accommodated in the vicinity of the, phenol ring of Tyr337. The structural data clearly show analogous, coordination of Ortho-7 and obidoxime within the active-site gorge of, AChE. Different ability to reactivate AChE inhibited by tabun is shown in, end-point reactivation experiments where HI-6, Ortho-7 and obidoxime, showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of, HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may, be explained by the differential binding of the oximes in the PAS and, active-site gorge of AChE.

About this Structure

2GYU is a Single protein structure of sequence from Mus musculus with NAG, HI6, P4G and P6G as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Full crystallographic information is available from OCA.

Reference

Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates., Ekstrom F, Pang YP, Boman M, Artursson E, Akfur C, Borjegren S, Biochem Pharmacol. 2006 Aug 28;72(5):597-607. Epub 2006 Jul 31. PMID:16876764

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