The influence of the N-terminal residues 203-214 and the linker domain on motions in the human topoisomerase I-DNA complex has been investigated by comparing the molecular dynamics simulations of the system with (topo70) or without (topo58/6.3) these regions. Topo58/6.3 is found to fluctuate more than topo70, indicating that the presence of the N-terminal residues and the linker domain dampen the core and C-terminal fluctuations. The simulations also show that residues 203-207 and the linker domain participate in a network of correlated movements with key regions of the enzyme, involved in the human topoisomerase I catalytic cycle, providing a structural-dynamical explanation for the better DNA relaxation activity of topo70 when compared to topo58/6.3. The data have been examined in relation to a wealth of biochemical, site-directed mutagenesis and crystallographic data on human topoisomerase I. The simulations finally show the occurrence of a network of direct and water mediated hydrogen bonds in the proximity of the active site, and the presence of a water molecule in the appropriate position to accept a proton from the catalytic Tyr-723 residue, suggesting that water molecules have an important role in the stabilization and function of this enzyme.

Chillemi, G., Redinbo, M., Bruselles, A., Desideri, A. (2004). Role of the linker domain and the 203-214 N-terminal residues in the human topoisomerase I DNA complex dynamics. BIOPHYSICAL JOURNAL, 87(6), 4087-4097 [10.1529/biophysj.104.044925].

Role of the linker domain and the 203-214 N-terminal residues in the human topoisomerase I DNA complex dynamics

DESIDERI, ALESSANDRO
2004-01-01

Abstract

The influence of the N-terminal residues 203-214 and the linker domain on motions in the human topoisomerase I-DNA complex has been investigated by comparing the molecular dynamics simulations of the system with (topo70) or without (topo58/6.3) these regions. Topo58/6.3 is found to fluctuate more than topo70, indicating that the presence of the N-terminal residues and the linker domain dampen the core and C-terminal fluctuations. The simulations also show that residues 203-207 and the linker domain participate in a network of correlated movements with key regions of the enzyme, involved in the human topoisomerase I catalytic cycle, providing a structural-dynamical explanation for the better DNA relaxation activity of topo70 when compared to topo58/6.3. The data have been examined in relation to a wealth of biochemical, site-directed mutagenesis and crystallographic data on human topoisomerase I. The simulations finally show the occurrence of a network of direct and water mediated hydrogen bonds in the proximity of the active site, and the presence of a water molecule in the appropriate position to accept a proton from the catalytic Tyr-723 residue, suggesting that water molecules have an important role in the stabilization and function of this enzyme.
2004
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
DNA topoisomerase; amino terminal sequence; article; carboxy terminal sequence; catalysis; crystallography; enzyme active site; enzyme activity; enzyme stability; hydrogen bond; molecular dynamics; molecular model; protein domain; site directed mutagenesis; Amino Acids; Binding Sites; Computer Simulation; DNA; DNA Topoisomerases, Type I; Enzyme Activation; Humans; Hydrogen Bonding; Kinetics; Models, Chemical; Models, Molecular; Molecular Conformation; Motion; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship
Chillemi, G., Redinbo, M., Bruselles, A., Desideri, A. (2004). Role of the linker domain and the 203-214 N-terminal residues in the human topoisomerase I DNA complex dynamics. BIOPHYSICAL JOURNAL, 87(6), 4087-4097 [10.1529/biophysj.104.044925].
Chillemi, G; Redinbo, M; Bruselles, A; Desideri, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/31848
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