Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex.
BACKGROUND: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2880615?pdf=render |
| _version_ | 1811269791372017664 |
|---|---|
| author | Giordano Mancini Ilda D'Annessa Andrea Coletta Nico Sanna Giovanni Chillemi Alessandro Desideri |
| author_facet | Giordano Mancini Ilda D'Annessa Andrea Coletta Nico Sanna Giovanni Chillemi Alessandro Desideri |
| author_sort | Giordano Mancini |
| collection | DOAJ |
| description | BACKGROUND: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death. METHODOLOGY/PRINCIPAL FINDINGS: Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain) that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed. CONCLUSIONS/SIGNIFICANCE: Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in both short-range interactions and long-range protein domain communications. |
| first_indexed | 2024-04-12T21:49:27Z |
| format | Article |
| id | doaj.art-207977249e72408f9517a5e719448846 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T21:49:27Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-207977249e72408f9517a5e7194488462022-12-22T03:15:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-01-0156e1093410.1371/journal.pone.0010934Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex.Giordano ManciniIlda D'AnnessaAndrea ColettaNico SannaGiovanni ChillemiAlessandro DesideriBACKGROUND: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death. METHODOLOGY/PRINCIPAL FINDINGS: Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain) that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed. CONCLUSIONS/SIGNIFICANCE: Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in both short-range interactions and long-range protein domain communications.http://europepmc.org/articles/PMC2880615?pdf=render |
| spellingShingle | Giordano Mancini Ilda D'Annessa Andrea Coletta Nico Sanna Giovanni Chillemi Alessandro Desideri Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. PLoS ONE |
| title | Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. |
| title_full | Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. |
| title_fullStr | Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. |
| title_full_unstemmed | Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. |
| title_short | Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex. |
| title_sort | structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase i dna complex |
| url | http://europepmc.org/articles/PMC2880615?pdf=render |
| work_keys_str_mv | AT giordanomancini structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex AT ildadannessa structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex AT andreacoletta structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex AT nicosanna structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex AT giovannichillemi structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex AT alessandrodesideri structuralanddynamicaleffectsinducedbytheanticancerdrugtopotecanonthehumantopoisomeraseidnacomplex |