title: Domains of human topoisomerase I and associated functions.
abstract: Human topoisomerase I can be divided into four domains based on homology alignments, physical properties, sensitivity to limited proteolysis, and fragment complementation studies. Roughly the first 197 amino acids represent the N-terminal domain that appears to be devoid of secondary structure and is likely important for targeting the enzyme to its sites of action within the nucleus of the cell. The core domain encompasses residues approximately 198 to approximately 651, is involved in catalysis, and is important for the preferential binding of the enzyme to supercoiled DNA. The C-terminal domain extends from residue approximately 697 to the end of the protein at residue 765 and contains the catalytically important active site tyrosine at position 723. The core and C-terminal domains are connected by a poorly conserved, protease-sensitive linker domain (residues approximately 652 to approximately 696) that has been implicated in DNA binding and may influence how long the enzyme remains in the nicked stated. Mutations that confer resistance to the topoisomerase I poison camptothecin are located in the core and C-terminal domains and presumably identify residues important for drug binding.
authors.affiliation: Department of Microbiology School of Medicine, University of Washington, Seattle 98195, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Champoux
mesh_terms: D001665:Binding Sites; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin