title: The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase.
abstract: The anticancer prodrug CPT-11 is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. The 2.6 angstroms resolution crystal structure of its complex with Torpedo californica acetylcholinesterase (TcAChE) demonstrates that CPT-11 binds to TcAChE and spans its gorge similarly to the Alzheimer drug, Aricept. The crystal structure clearly reveals the interactions, which contribute to the inhibitory action of CPT-11. Modeling of the complexes of CPT-11 with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug, shows how binding to either of the two enzymes yields a productive substrate-enzyme complex.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Harel
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Boris
authors.initials: B
authors.lastname: Brumshtein
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Randy M
authors.initials: RM
authors.lastname: Wadkins
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry; D043182:Carboxylesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006868:Hydrolysis; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011817:Rabbits; D014101:Torpedo
chemical_list: D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D000077146:Irinotecan; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002166:Camptothecin