Journal:Neuropharmacology:2
From Proteopedia
Computational Studies on Cholinesterases: Strengthening our Understanding of the Integration of Structure, Dynamics and FunctionJoel L. Sussman and Israel Silman [1] Molecular Tour Solution of the crystal structure of Torpedo californica acetylcholinesterase (TcAChE) in 1991 (Sussman et al., 1991)[2], revealed a three-dimensional structure that was wholly unanticipated. Despite the fact that AChE is one of the most rapid enzymes known, operating at a speed approaching diffusion control (Bazelyansky et al., 1986;[3] Rosenberry, 1975[4]), its active site is deeply buried, at the bottom of a long and narrow gorge, whose cross-section, at its narrowest point, is significantly smaller than the cross-section of the quaternary group of acetylcholine (ACh). Subsequent solution of the crystal structures of mouse (m) (Bourne et al., 1995[5]), Electrophorus electricus (Ee) (Bourne et al., 1999;[6] Raves et al., 1998[7]), human (h) (Cheung et al., 2012;[8] Kryger et al., 2000[9]), Drosophila melanogaster (Dm) (Harel et al., 2000[10]), Bungarus fasciatus (Bf) (Bourne et al., 2015[11]), and Anopheles gambiae (Ag) (Cheung et al., 2018;[12] Han et al., 2018[13]) AChEs, as well as that of human serum butyrylcholinesterase (hBChE) (Nicolet et al., 2003[14]), revealed highly homologous structures. The crystal structures of the cholinesterases (ChEs) raised cogent questions with respect to the coupling of the structure of the enzymes, together with their dynamics, to their catalytic activity, and to the way in which inhibitors, some of which are large and rigid, bind to, and disassociate from them. These topics have been covered extensively in earlier reviews (Silman and Sussman, 2008;[15] Xu et al., 2017[16]). However, as computing power has continued to grow, databases have expanded, and increasingly sophisticated algorithms have been developed, problems become accessible that had previously seemed unapproachable (Fuxreiter, 2015[17]). In the following, after briefly surveying the structure and dynamics of the ChEs, taking TcAChE as the prototypic case, we wish to briefly present and discuss some recent studies that cover various aspects of these topics. Crystal structure of a hAChE designed using the PROSS algorithm, and expressed in E coli. It is displayed in ribbon form, colored from the N-terminus to the C-terminus in a spectrum going from blue to red. The 51 amino acids that were mutated on the basis of the prediction of the PROSS algorithm are shown as magenta spheres. Change in orientation of the catalytic histidine (H438) in the N322E/E325G mutant. Carbon atoms of H438 and E325 are shown as green sticks for the wild-type conformation. Carbon atoms of H438 and E322, as well as of the oxyanion hole residues - G116, G117 and A199 - are shown as cyan sticks for the mutant. In both cases, oxygens are coded in red, and nitrogens in blue. The OP moiety covalently attached to S198 in the mutant is displayed as balls, with the phosphorus in orange, the oxygens in red and the carbons in cyan. H-bonds are shown as white dashed lines. Docking and MD simulation for interaction of BSF and PMSF with TcAChE and mAChE. In all four scenes two copies of the ligand are displayed. One shows the position of the ligand after docking alone (blue), and the other shows the position after docking followed by MD simulation (orange). It should be noted that the orientations of the amino-acid side-chains displayed are those seen prior to the MD simulations.
Effect of ethylene glycol oligomers (PEGs) on the positioning of the ligand in the crystal structure of the methylene blue/''Tc''AChE complex crystallized from PEG200. Three PEGs are shown in red, methylene blue in blue, and conserved aromatic residues lining the active-site gorge in green. A highly conserved H2O molecule, shown as a yellow sphere, also affects the positioning of the ligand. Active-site gorge in the original and updated structures of native DmAChE. Residues of the catalytic triad (E367/H480/S238), of the oxyanion hole (G150/G151/Al239), and key residues of the peripheral site (W321), acyl-binding pocket (W271), and choline-binding pocket (W83), are represented as sticks, with carbons in white, nitrogens in blue, and oxygens in red. The alternative conformation of W83 is depicted with carbons in cyan. The acetyl (ACT) is represented as balls and sticks. H-bonds are depicted as black dashes, with distances in Å. References
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