Sandbox 3

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Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) for quaternary ligands were investigated by x-ray crystallography and photoaffinity labeling. Crystal structures of complexes with ligands were determined at 2.8-A resolution. In a complex with edrophonium, and quaternary nitrogen of the ligand interacts with the indole of Trp-84, and its m-hydroxyl displays bifurcated hydrogen bonding to two members of the catalytic triad, Ser-200 and His-440. In a complex with tacrine, the acridine is stacked against the indole of Trp-84. The bisquaternary ligand decamethonium is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of Trp-84 and the other to that of Trp-279, near the top of the gorge. The only major conformational difference between the three complexes is in the orientation of the phenyl ring of Phe-330. In the decamethonium complex it lies parallel to the surface of the gorge; in the other two complexes it is positioned to make contact with the bound ligand. This close interaction was confirmed by photoaffinity labelling by the photosensitive probe 3H-labeled p-(N,N-dimethylamino)benzenediazonium fluoroborate, which labeled, predominantly, Phe-330 within the active site. Labeling of Trp-279 was also observed. One mole of label is incorporated per mole of AcChoEase inactivated, indicating that labeling of Trp-279 and that of Phe-330 are mutually exclusive. The structural and chemical data, together, show the important role of aromatic groups as binding sites for quaternary ligands, and they provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site and Trp-279 to the "peripheral" anionic site.
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Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) with the bisquaternary ligand decamethonium (DME). DME is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of W84 and the other to that of W279, near the top of the gorge, i.e. the "peripheral" anionic site. The only major conformational change in the structure AChE is in the orientation of F330 which lies parallel to the surface of the gorge, near the cationic binding site of AChE which contains the catalytic triad S200, E327 & H440.

Revision as of 10:09, 27 June 2008

Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) with the bisquaternary ligand decamethonium (DME). DME is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of W84 and the other to that of W279, near the top of the gorge, i.e. the "peripheral" anionic site. The only major conformational change in the structure AChE is in the orientation of F330 which lies parallel to the surface of the gorge, near the cationic binding site of AChE which contains the catalytic triad S200, E327 & H440.

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