ArticleNucleic acids research2008
Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.
Article in Nucleic acids research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 54 citations in OpenAlex.
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- Dynamozones are the most obvious sign of the evolution of conformational dynamics in HIV-1 protease.Scientific reports · 2023Article
- Exploring the dynamic mechanism of allosteric drug SHP099 inhibiting SHP2Molecular diversity · 2021Article
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- Molecular modeling and molecular dynamics simulation studies on thyroid hormone receptor from Rattus norvegicus: role of conserved water molecules.Journal of molecular modeling · 2021Article
- The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants.Scientific reports · 2021Article
- Mathematical modeling and computational prediction of cancer drug resistance.Briefings in bioinformatics · 2018Review
- Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism.Scientific reports · 2017Article
- Structural Mechanism behind Distinct Efficiency of Oct4/Sox2 Proteins in Differentially Spaced DNA Complexes.PloS one · 2016Article
- Structural and Dynamic Characterization of the C313Y Mutation in Myostatin Dimeric Protein, Responsible for the "Double Muscle" Phenotype in Piedmontese Cattle.Frontiers in genetics · 2016Article
- Recovery of the poisoned topoisomerase II for DNA religation: coordinated motion of the cleavage core revealed with the microsecond atomistic simulation.Nucleic acids research · 2015Article
- Simulations of DNA topoisomerase 1B bound to supercoiled DNA reveal changes in the flexibility pattern of the enzyme and a secondary protein-DNA binding site.Nucleic acids research · 2014Article
- Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.Nucleic acids research · 2013Article
- Molecular mechanism of the camptothecin resistance of Glu710Gly topoisomerase IB mutant analyzed in vitro and in silico.Molecular cancer · 2013Article
- Structural and functional interactions of the prostate cancer suppressor protein NKX3.1 with topoisomerase I.The Biochemical journal · 2013Article
- Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant.PloS one · 2013Article
- Characterization of DNA topoisomerase-1 in Spodoptera exigua for toxicity evaluation of camptothecin and hydoxy-camptothecin.PloS one · 2013Article
- Solvent dependency of the UV-Vis spectrum of indenoisoquinolines: role of keto-oxygens as polarity interaction probes.PloS one · 2013Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The role of Thr729 in modulating the enzymatic function of human topoisomerase I has been characterized by molecular dynamics (MD) simulation. In detail, the structural-dynamical behaviour of the Thr729Lys and the Thr729Pro mutants have been characterized because of their in vivo and in vitro functional properties evidenced in the accompanying paper. Both mutants can bind to the DNA substrate and are enzymatically active, but while Thr729Lys is resistant even at high concentration of the camptothecin (CPT) anti-cancer drug, Thr729Pro shows only a mild reduction in drug sensitivity and in DNA binding. MD simulations show that the Thr729Lys mutation provokes a structural perturbation of the CPT-binding pocket. On the other hand, the Thr729Pro mutant maintains the wild-type structural scaffold, only increasing its rigidity. The simulations also show the complete abolishment, in the Thr729Lys mutant, of the protein communications between the C-terminal domain (where the active Tyr723 is located) and the linker domain, that plays an essential role in the control of the DNA rotation, thus explaining the distributive mode of action displayed by this mutant.
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