2WU3

CRYSTAL STRUCTURE OF MOUSE ACETYLCHOLINESTERASE IN COMPLEX WITH FENAMIPHOS AND HI-6

Summary for 2WU3

• Entry DOI: 10.2210/pdb2wu3/pdb
• Related: 1C2B 1C2O 1J06 1J07 1KU6 1MAA 1MAH 1N5M 1N5R 1Q83 1Q84 2C0P 2C0Q 2H9Y 2HA0 2HA2 2HA3 2HA4 2HA5 2HA6 2HA7 2JEY 2JEZ 2JF0 2JGE 2JGF 2JGG 2JGH 2JGI 2JGJ 2JGK 2JGL 2JGM 2WHP 2WHQ 2WHR 2WLS 2WU4
• Descriptor: ACETYLCHOLINESTERASE, 4-(AMINOCARBONYL)-1-[({2-[(E)-(HYDROXYIMINO)METHYL]PYRIDINIUM-1-YL}METHOXY)METHYL]PYRIDINIUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: acetylcholinesterase, alternative splicing, fenamiphos, glycoprotein, hydrolase, membrane, neurotransmitter degradation, serine esterase, synapse, hi-6
• Biological source: MUS MUSCULUS (MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 122187.59

Authors

Hornberg, A.,Artursson, E.,Warme, R.,Pang, Y.-P.,Ekstrom, F. (deposition date: 2009-09-28, release date: 2009-10-20, Last modification date: 2023-12-20)

Primary citation

Hornberg, A.,Artursson, E.,Warme, R.,Pang, Y.-P.,Ekstrom, F.
Crystal Structures of Oxime-Bound Fenamiphos-Acetylcholinesterases: Reactivation Involving Flipping of the His447 Ring to Form a Reactive Glu334-His447-Oxime Triad.
Biochem.Pharm., 79:507-, 2010

PubMed Abstract: 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-N,N'-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 Mus musculus acetylcholinesterase inhibited by the insecticide fenamiphos (fep-mAChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and 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-mAChE complex adopt conformations that are similar to those in the apo mAChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-mAChE 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.

PubMed: 19732756
DOI: 10.1016/J.BCP.2009.08.027

Experimental method

X-RAY DIFFRACTION (2.7 Å)