title: Role of flexibility and long range communication on the function of human topoisomerase I.
abstract: Eukaryotic topoisomerase I is an essential enzyme that regulates the changes in DNA topology, relaxing the superhelical tension associated with DNA replication, transcription and recombination. Human topoisomerase I is of significant medical interest being the only target of the antitumor drug camptothecin. The enzyme undergoes large conformational changes during its catalytic cycle and the knowedge of the degree of flexibility of the different regions provides an useful guide to the understanding of such movements. Molecular dynamics simulation is a well consolidated method for the investigation of structural and dynamic properties of proteins and nucleic acids and has been successfully applied to study the dynamical properties of the DNA-human topoisomerase complex. This review highlights some structural and dynamic properties of topoisomerase, obtained by MD simulations, that permits to explain the importance of flexibility in the modulation of the functional properties of the enzyme and in the transmission of communication between domains located far away one from each other.
authors.affiliation: CASPUR Interuniversities Consortium for Supercomputing Applications, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.forename: Paola
authors.initials: P
authors.lastname: Fiorani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bruselles
authors.forename: Silvia
authors.initials: S
authors.lastname: Castelli
authors.forename: Alessia
authors.initials: A
authors.lastname: Campagna
authors.forename: Ofelia
authors.initials: O
authors.lastname: Sarra
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tesauro
authors.forename: Monica
authors.initials: M
authors.lastname: Fiorentini
authors.forename: Oscar
authors.initials: O
authors.lastname: Vassallo
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.forename: Sabrina
authors.initials: S
authors.lastname: Santoleri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism*; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004278:DNA, Superhelical; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin