ArticleNucleic acids research2005
Rotation of DNA around intact strand in human topoisomerase I implies distinct mechanisms for positive and negative supercoil relaxation.
Article in Nucleic acids research, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 29 citations in OpenAlex.
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- A CHK1-mediated phosphorylation switch suppresses human Topoisomerase 1-associated genomic instability.The EMBO journal · 2026Article
- Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states.Nature communications · 2022Article
- Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development.ChemMedChem · 2020Article
- Topoisomerase IB: a relaxing enzyme for stressed DNA.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Swapping of The N-Terminal Domain of Human Topoisomerase 1B with the CorrespondingReports of biochemistry & molecular biology · 2020Article
- Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant.PloS one · 2013Article
- A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I.Nucleic acids research · 2011Article
- Free energy calculations reveal rotating-ratchet mechanism for DNA supercoil relaxation by topoisomerase IB and its inhibition.Biophysical journal · 2010Article
- Evidence of the crucial role of the linker domain on the catalytic activity of human topoisomerase I by experimental and simulative characterization of the Lys681Ala mutant.Nucleic acids research · 2009Article
- Role of a tryptophan anchor in human topoisomerase I structure, function and inhibition.The Biochemical journal · 2008Article
- Molecular dynamics simulations of nucleic acid-protein complexes.Current opinion in structural biology · 2008Review
- The open state of human topoisomerase I as probed by molecular dynamics simulation.Nucleic acids research · 2007Article
- Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal.Nucleic acids research · 2007Article
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2 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Topoisomerases are enzymes of quintessence to the upkeep of superhelical DNA, and are vital for replication, transcription and recombination. An atomic-resolution model for human topoisomerase I in covalent complex with DNA is simulated using molecular dynamics with external potentials that mimic torque and bias the DNA duplex downstream of a single-strand cut to rotate around the intact strand, according to the prevailing enzymatic mechanism. The simulations reveal the first dynamical picture of how topoisomerase accommodates large-scale motion of DNA as it changes its supercoiling state, and indicate that relaxation of positive and negative supercoils are fundamentally different. To relax positive supercoils, two separate domains (the 'lips') of the protein open up by about 10-14 A, whereas to relax negative supercoils, a continuous loop connecting the upper and lower parts (and which was a hinge for opening the lips) stretches about 12 A while the lips remain unseparated. Normal mode analysis is additionally used to characterize the functional flexibility of the protein. Remarkably, the same combination of low-frequency eigenvectors exhibit the dominant contribution for both rotation mechanisms through a see-saw motion. The simulated mechanisms suggest mutations to control the relaxation of either type of supercoiling selectively and advance a hypothesis for the debated role of the N-terminal domain in supercoil relaxation.
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