Aromatic gorge

The PAS is located at the rim of the aromatic gorge, on the protein s surface. It spans six AChE residues Tyr 72, Tyr 124, Glu 285 and Tip 286, on one side of the gorge entrance, and Asp 74 and Tyr 341, on its opposite side. Its core is comprised of Tip 286 and Asp 74, which accommodates many distinct ligands. BChE also has a PAS, but its relatively aromatic content and the response upon ligand-binding differ significantly from those of AChE. 

Ripoll, D.R., Faerman, C.H., Axelson, P.H., Silman, I. and Sussman, J.L. (1993) An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase. Proceedings of the National Academy of Sciences USA 90, 5128-5132. 

Fig 5-2. This schematic ribbon diagram shows the structure of Torpedo californica acetylcholinesterase. The diagram is color-coded green the 537-amino acid polypeptide of the enzyme monomer pink the 14 aromatic residues that line the deep aromatic gorge leading to the active site and gold and blue a model of the natural substrate for acetylcholinesterase, the neurotransmitter acetylcholine, docked in the active site. Reprinted with permission from Sussman JL, Silman I. Acetylcholinesterase Structure and use as a model for specific cation-protein interactions. Curr Opin Struct Biol. 1992 2 724. 

Fig. 11.2. Schematic representation of the primary structure of secreted AChE B of N. brasiliensis in comparison with that of Torpedo californica, for which the three-dimensional structure has been resolved. The residues in the catalytic triad (Ser-His-Glu) are depicted with an asterisk, and the position of cysteine residues and the predicted intramolecular disulphide bonding pattern common to cholinesterases is indicated. An insertion of 17 amino acids relative to the Torpedo sequence, which would predict a novel loop at the molecular surface, is marked with a black box. The 14 aromatic residues lining the active-site gorge of the Torpedo enzyme are illustrated. Identical residues in the nematode enzyme are indicated in plain text, conservative substitutions are boxed, and non-conservative substitutions are circled. The amino acid sequence of AChE C is 90% identical to AChE B, and differs only in the features illustrated in that Thr-70 is substituted by Ser.

The initial solution of the crystal structure of the Torpedo enzyme [28], followed by the mammalian AChE structure [29], revealed that the active center serine lies at the base of a rather narrow gorge that is lined heavily with aromatic residues (Fig. 11-6). The enzyme carries a net negative charge, and an electrostatic dipole is oriented on the enzyme to facilitate diffusional entry of cationic ligands. Crystal structures of several inhibitors in a complex with AChE also have been elucidated [25]. 

Harel, M., Sussman, J.L. Quaternary Hgand Binding to Aromatic Residues in the Active Site Gorge of Acetylcholinesterase. Proc. Natl. Acad. Sci. USA 1993, 90, 9031-9035. 

Hard M, Schalk I, Ehretsabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL (1993) Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 90 9031-9035... 

Kaplan, D., Ordentlich, A., Barak, D., Ariel, N., Kronman, C., Velan, B., Shafferman, A. (2001). Does butyrylization of acetylcholinesterase through substitution of the six divergent aromatic amino acids in the active center gorge generate an enzyme mimic of butyrylcholinesterase Biochemistry 40 7433-45. 

The three-dimensional structure of AChE from the electric organ of Torpedo californica has been established. One interesting feature is that the active site is embedded in a gorge of 20 A that reaches halfway into the protein. The postulated anionic site , theoretically invoked to bind the quaternary ammonium ion of ACh, appears to be represented by aromatic amino acids in the gorge itself these and charges in the active center are believed to stabilize the choline group. In addition, some inhibitions, such as that due... 

Figure 24. Close-up view of the active site of AChE with the triad in yellow, the aromatic side chains coating the deep gorge in red, and a model of the acetylcholine transition state in pink.

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