6fld

Carbamylated T. californica acetylcholineterase bound to uncharged hybrid reactivator 1

spinqualitylabelsall models 6fld, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fld is a 1 chain structure with sequence from Tetronarce californica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: 1PG, BXT, CL, DQ5, EDO, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACES_TETCF Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions. Publication Abstract from PubMed Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active-site, but they poorly distribute in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a non-quaternary oxime is also an undesired sub-micromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized, and, in line with the prediction, displayed a 10-fold decrease in inhibition, but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of a new generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication. Structure-based optimization of non-quaternary reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents.,Santoni G, de Sousa J, De la Mora E, Dias J, Jean L, Sussman JL, Silman I, Renard PY, Brown RCD, Weik M, Baati R, Nachon F J Med Chem. 2018 Aug 20. doi: 10.1021/acs.jmedchem.8b00592. PMID:30125110 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholinesterase 3D structures

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