Figure 2
(a) Five AChE protein structures used in the docking/rescoring calculations are aligned by key active site residues, [Human Xtal (5FPQ), Human Model (derived from 1B41), Mouse 2Y2V, Mouse 2WHP, and Mouse 5FPP]. The sidechains of several residues that mediate binding of oximes have significant spatial variability. Alternate conformations are shown in gold; Asp74, Trp86, Trp286, Trp337, and Trp341. The isopropyl tail (green) of the adduct is rotated by ~ 50° around the isopropyl-O–P bond, placing the methyl groups closer to the Trp86 sidechain. Reactivator design needs to account for the active site plasticity to prevent unproductive binding. Figure created with VMD60. (b) Key AChE active site residues with two putative nucleophilic reaction mechanisms. The in-line attack mechanism places the approaching oxime group at 180° to the Ser203 oxygen atom in the Ser-O–P=O plane. The serine residue then becomes the leaving group, and the phosphate-oxime complex can leave the active site or recombine. In the adjacent attack scenario, there are two possible leaving groups, Ser203 and the isopropyl group. If the isopropyl group leaves then the enzyme is not reactivatable. A close interaction of the isopropyl group with the indole sidechain of Trp86 will fill the space available for binding and reduces the possibility of adjacent attack as seen in the 5FPP crystal structure.
