Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations Export

@article{citeulike:3774084, 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. 10.1093/nar/gkn558}, author = {Chillemi, Giovanni and D'Annessa, Ilda and Fiorani, Paola and Losasso, Carmen and Benedetti, Piero and Desideri, Alessandro}, citeulike-article-id = {3774084}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/nar/gkn558}, citeulike-linkout-1 = {http://nar.oxfordjournals.org/cgi/content/abstract/36/17/5645}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18765473}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18765473}, day = {1}, doi = {10.1093/nar/gkn558}, journal = {Nucl. Acids Res.}, keywords = {cepa, cpt, topo}, month = {October}, number = {17}, pages = {5645--5651}, posted-at = {2008-12-11 17:22:50}, priority = {2}, title = {Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations}, url = {http://dx.doi.org/10.1093/nar/gkn558}, volume = {36}, year = {2008} }

TY - JOUR ID - citeulike:3774084 L3 - citeulike-article-id:3774084 N2 - 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. 10.1093/nar/gkn558 IS - 17 JF - Nucl. Acids Res. EP - 5651 TI - Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations VL - 36 SP - 5645 KW - cepa KW - cpt KW - topo AU - Chillemi, Giovanni AU - D'Annessa, Ilda AU - Fiorani, Paola AU - Losasso, Carmen AU - Benedetti, Piero AU - Desideri, Alessandro PY - 2008/10/01/ UR - http://dx.doi.org/10.1093/nar/gkn558 ER -