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Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design.

Ekström F, Hörnberg A, Artursson E, Hammarström LG, Schneider G, Pang YP
PLoS One 4 e5957 (2009)
Related entries: 2whp, 2whr

Cited: 49 times
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Abstract

Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.

Reviews - 2whq mentioned but not cited (1)

  1. Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning. Kovalevsky A, Blumenthal DK, Cheng X, Taylor P, Radić Z. Ann N Y Acad Sci 1378 41-49 (2016)

Articles - 2whq mentioned but not cited (4)

  1. Structure of HI-6*sarin-acetylcholinesterase determined by X-ray crystallography and molecular dynamics simulation: reactivator mechanism and design. Ekström F, Hörnberg A, Artursson E, Hammarström LG, Schneider G, Pang YP. PLoS One 4 e5957 (2009)
  2. Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking. Imramovsky A, Stepankova S, Vanco J, Pauk K, Monreal-Ferriz J, Vinsova J, Jampilek J. Molecules 17 10142-10158 (2012)
  3. Interaction kinetics of oximes with native, phosphylated and aged human acetylcholinesterase. Radić Z, Kalisiak J, Fokin VV, Sharpless KB, Taylor P. Chem Biol Interact 187 163-166 (2010)
  4. A Novel Multifunctional 5,6-Dimethoxy-Indanone-Chalcone-Carbamate Hybrids Alleviates Cognitive Decline in Alzheimer's Disease by Dual Inhibition of Acetylcholinesterase and Inflammation. Liu C, Sang Z, Pan H, Wu Q, Qiu Y, Shi J. Front Aging Neurosci 14 922650 (2022)


Reviews citing this publication (3)

  1. The value of novel oximes for treatment of poisoning by organophosphorus compounds. Worek F, Thiermann H. Pharmacol Ther 139 249-259 (2013)
  2. SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides. Gorecki L, Korabecny J, Musilek K, Malinak D, Nepovimova E, Dolezal R, Jun D, Soukup O, Kuca K. Arch Toxicol 90 2831-2859 (2016)
  3. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. Masson P, Nachon F. J Neurochem 142 Suppl 2 26-40 (2017)

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  12. Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad. Hörnberg A, Artursson E, Wärme R, Pang YP, Ekström F. Biochem Pharmacol 79 507-515 (2010)
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  23. Nerve Gas Simulant Sensing by a Uranyl-Salen Monolayer Covalently Anchored on Quartz Substrates. Trusso Sfrazzetto G, Millesi S, Pappalardo A, Tomaselli GA, Ballistreri FP, Toscano RM, Fragalà I, Gulino A. Chemistry 23 1576-1583 (2017)
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