Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.
Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.
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人拓扑异构酶I中的THR729通过改变蛋白质结构域的通信来调节抗癌耐药性，如分子动力学模拟所建议的那样。
DOI：
10.1093/nar/gkn558
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发表时间：
2008-10
影响因子：
14.9
通讯作者：
Desideri, Alessandro
中科院分区：
文献类型：
--
作者：
Chillemi, Giovanni;D'Annessa, Ilda;Fiorani, Paola;Losasso, Carmen;Benedetti, Piero;Desideri, Alessandro
Thr 729在调节人拓扑异构酶I的酶功能中的作用已经通过分子动力学（MD）模拟表征。详细地说，Thr 729 Lys和Thr 729 Pro突变体的结构动力学行为已被表征，因为它们的体内和体外功能特性在随附的论文中得到证明。这两种突变体都可以结合到DNA底物上，并且具有酶活性，但是尽管Thr 729 Lys即使在高浓度的喜树碱（CPT）抗癌药物下也具有抗性，但Thr 729 Pro仅显示出药物敏感性和DNA结合的轻度降低。MD模拟表明，Thr 729 Lys突变引起CPT结合口袋的结构扰动。另一方面，Thr 729 Pro突变体保持野生型结构支架，仅增加其刚性。模拟还显示完全废除，在Thr 729 Lys突变体中，C-末端结构域（活性Tyr 723所在的位置）和连接结构域之间的蛋白质通信，这在DNA旋转的控制中起着至关重要的作用，从而解释了该突变体所显示的作用的分布模式。
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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影响因子：
4.8
作者：
Fertala, J;Vance, JR;Bjornsti, MA
通讯作者：
Bjornsti, MA
影响因子：
3.6
作者：
Fiorani, P;Amatruda, JF;Benedetti, P
通讯作者：
Benedetti, P
DOI：
10.1073/pnas.242259599
发表时间：
2002-11-26
影响因子：
11.1
作者：
Staker, BL;Hjerrild, K;Stewart, L
通讯作者：
Stewart, L
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
14.9
作者：
Chillemi, G;Fiorani, P;Desideri, A
通讯作者：
Desideri, A