Journal:Neuropharmacology:2
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Computational approaches have proved valuable in elucidating structure/function relationships in the cholinesterases in the context of their unusual three-dimensional structure. In this review we survey several recent studies that have enhanced our understanding of how these enzymes function, and have utilized computational approaches both to modulate their activity and to improve the design of lead compounds for their inhibition. | Computational approaches have proved valuable in elucidating structure/function relationships in the cholinesterases in the context of their unusual three-dimensional structure. In this review we survey several recent studies that have enhanced our understanding of how these enzymes function, and have utilized computational approaches both to modulate their activity and to improve the design of lead compounds for their inhibition. | ||
Solution of the crystal structure of ''Torpedo californica'' acetylcholinesterase (''Tc''AChE) in 1991 (Sussman ''et al.,'' 1991)<ref name="Sussman">PMID:1678899</ref>, 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;<ref name="Bazelyansky">PMID:3954986</ref> Rosenberry, 1975<ref name="Rosenberry">PMID:891</ref>), 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<ref name="Bourne">PMID:8521480</ref>), ''Electrophorus electricus'' (''Ee'') (Bourne ''et al.,'' 1999;<ref name="Bourne1">PMID:10521413</ref> Raves ''et al.,'' 1998<ref name="Raves">DOI:10.1007/978-1-4899-1540-5_97</ref>), human (h) (Cheung ''et al.,'' 2012;<ref name="Cheung">PMID:23035744</ref> Kryger ''et al.,'' 2000<ref name="Kryger">PMID:11053835</ref>), ''Drosophila melanogaster'' (''Dm'') (Harel ''et al.,'' 2000<ref name="Harel">PMID:10892800</ref>), ''Bungarus fasciatus'' (''Bf'') (Bourne ''et al.,'' 2015<ref name="Bourne2">PMID:25411244</ref>), and ''Anopheles gambiae'' (''Ag'') (Cheung ''et al.,'' 2018;<ref name="Cheung1">PMID:29276037</ref> Han ''et al.,'' 2018<ref name="Han">PMID:28247978</ref>) AChEs, as well as that of human serum butyrylcholinesterase (hBChE) (Nicolet ''et al.,'' 2003<ref name="Nicolet">PMID:12869558</ref>), 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;<ref name="Silman">PMID:18586019</ref> Xu ''et al.,'' 2017<ref name="Xu">PMID:28796192</ref>). 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<ref name="Fuxreiter">DOI:10.1201/b17979</ref>). In the following, after briefly surveying the structure and dynamics of the ChEs, taking ''Tc''AChE as the prototypic case, we wish to briefly present and discuss some recent studies that cover various aspects of these topics. | Solution of the crystal structure of ''Torpedo californica'' acetylcholinesterase (''Tc''AChE) in 1991 (Sussman ''et al.,'' 1991)<ref name="Sussman">PMID:1678899</ref>, 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;<ref name="Bazelyansky">PMID:3954986</ref> Rosenberry, 1975<ref name="Rosenberry">PMID:891</ref>), 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<ref name="Bourne">PMID:8521480</ref>), ''Electrophorus electricus'' (''Ee'') (Bourne ''et al.,'' 1999;<ref name="Bourne1">PMID:10521413</ref> Raves ''et al.,'' 1998<ref name="Raves">DOI:10.1007/978-1-4899-1540-5_97</ref>), human (h) (Cheung ''et al.,'' 2012;<ref name="Cheung">PMID:23035744</ref> Kryger ''et al.,'' 2000<ref name="Kryger">PMID:11053835</ref>), ''Drosophila melanogaster'' (''Dm'') (Harel ''et al.,'' 2000<ref name="Harel">PMID:10892800</ref>), ''Bungarus fasciatus'' (''Bf'') (Bourne ''et al.,'' 2015<ref name="Bourne2">PMID:25411244</ref>), and ''Anopheles gambiae'' (''Ag'') (Cheung ''et al.,'' 2018;<ref name="Cheung1">PMID:29276037</ref> Han ''et al.,'' 2018<ref name="Han">PMID:28247978</ref>) AChEs, as well as that of human serum butyrylcholinesterase (hBChE) (Nicolet ''et al.,'' 2003<ref name="Nicolet">PMID:12869558</ref>), 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;<ref name="Silman">PMID:18586019</ref> Xu ''et al.,'' 2017<ref name="Xu">PMID:28796192</ref>). 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<ref name="Fuxreiter">DOI:10.1201/b17979</ref>). In the following, after briefly surveying the structure and dynamics of the ChEs, taking ''Tc''AChE as the prototypic case, we wish to briefly present and discuss some recent studies that cover various aspects of these topics. | ||
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| + | <scene name='85/857780/Cv/2'>Crystal structure of a hAChE designed using the PROSS algorithm</scene>, 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. | ||
Docking and MD simulation for interaction of BSF and PMSF with ''Tc''AChE 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. | Docking and MD simulation for interaction of BSF and PMSF with ''Tc''AChE 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. | ||
Revision as of 15:30, 2 August 2020
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This page complements a publication in scientific journals and is one of the Proteopedia's Interactive 3D Complement pages. For aditional details please see I3DC.
