4a23

Mus musculus Acetylcholinesterase in complex with racemic C5685

spinqualitylabelsall models 4a23, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4a23 is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: C56, C57, PE4, PEG Related: 2jgh, 2whq, 1mah, 1maa, 2ha6, 2c0q, 2jgg, 2jgl, 2xug, 1q84, 2xud, 2jgm, 2xuj, 2jge, 1q83, 2wls, 2xup, 2xuk, 1c2b, 2y2u, 2ha3, 2ha0, 2wu3, 2xuf, 2jey, 2jgi, 1n5r, 2xuh, 2jgj, 1j06, 2c0p, 2jf0, 2xuo, 2h9y, 2whr, 2xui, 1n5m, 2ha5, 2ha2, 2xuq, 2whp, 2jez, 2jgk, 1ku6, 2ha4, 1j07, 2ha7, 2jgf, 2y2v, 2wu4, 1c2o, 4a16 Activity: Acetylcholinesterase, with EC number 3.1.1.7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ACES_MOUSE] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Publication Abstract from PubMed Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685*mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators. Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling.,Berg L, Andersson CD, Artursson E, Hornberg A, Tunemalm AK, Linusson A, Ekstrom F PLoS One. 2011;6(11):e26039. Epub 2011 Nov 30. PMID:22140425 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholinesterase 3D structures 3D structures of acetylcholinesterase

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