4bdt | pdb_00004bdt
Human acetylcholinesterase in complex with huprine W and fasciculin 2
Structural highlights
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.[1] [2] [3] [4] [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. Publication Abstract from PubMedThe multifunctional nature of Alzheimer's disease calls for multi-target directed ligands (MTDLs) able to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually based on cholinesterase inhibitors (e.g., tacrine or huprine) coupled to another active molecule aimed at a different target. To aid in the design of these MTDLs we report the crystal structures of human acetylcholinesterase (hAChE) in complex with FAS-2 and a hydroxylated derivative of huprine (huprine W), and of human butyrylcholinesterase (hBChE) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, pi-pi/cation-pi interactions with Trp86(82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine. Huprine W forms additional interactions with hAChE which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE able to accommodate the chlorine substituent. Crystal Structures of Human Cholinesterases in Complex with Huprine W and Tacrine: Elements of Specificity for Anti-Alzheimer's Drugs Targeting Acetyl- and Butyrylcholinesterase.,Nachon F, Carletti E, Ronco C, Trovaslet M, Nicolet Y, Jean L, Renard PY Biochem J. 2013 May 17. PMID:23679855[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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