2x8b

Crystal structure of human acetylcholinesterase inhibited by aged tabun and complexed with fasciculin-II

spinqualitylabelsall models 2x8b, resolution 2.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2x8b is a 2 chain structure with sequence from Dendroaspis angusticeps and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, NAG, SO4, UNX NonStd Res: SEN Related: 1fsc, 1mah, 1ku6, 2clj, 1b41, 1puv, 1fss, 1puw, 1vzj, 1f8u Activity: Acetylcholinesterase, with EC number 3.1.1.7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis. [TXFA2_DENAN] This three-finger toxin selectively binds and inhibits with a 1:1 stoichiometry the mammalian and electric fish acetylcholinesterase (AChE) at picomolar concentrations. It is highly specific for the peripheral site on acetylcholinesterase. It has been called fasciculin since after injection into mice it cause severe, generalized and long-lasting (5-7 hours) fasciculations. The whole venom has anticoagulant activity, and the various components seem to act synergistically. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct. We solved the X-ray structure of aged tabun-hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase. Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge. This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE. Structural Evidence That Human Acetylcholinesterase Inhibited by Tabun Ages through O-Dealkylation.,Carletti E, Colletier JP, Dupeux F, Trovaslet M, Masson P, Nachon F J Med Chem. 2010 Apr 21. PMID:20408548 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholinesterase 3D structures Fasciculin

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