Transient non-native hydrogen bonds promote activation of a signaling protein.
Transient non-native hydrogen bonds promote activation of a signaling protein.
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DOI：
10.1016/j.cell.2009.11.022
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发表时间：
2009-12-11
期刊：
影响因子：
64.5
通讯作者：
Kern D
中科院分区：
文献类型：
--
作者：
Gardino AK;Villali J;Kivenson A;Lei M;Liu CF;Steindel P;Eisenmesser EZ;Labeikovsky W;Wolf-Watz M;Clarkson MW;Kern D
磷酸化是生物学中最常用的信号传导机制之一。然而，人们对非活性状态和活性状态之间的分子转变途径知之甚少。在这里，我们定量表征的自由能景观激活的信号蛋白氮调节蛋白C（NtrC）连接功能蛋白质动力学磷酸化依赖的激活蛋白质折叠。我们表明，只有很少填充，预先存在的活性构象能够被磷酸化。原子细节的复杂的构象转变的途径，推断从分子动力学模拟实验测试在这里通过NMR动力学实验。我们发现，在激活过程中的本地稳定接触的损失是由非本地瞬态原子相互作用在过渡期间补偿。结果表明，计算与实验相结合的力量，以解开原子的细节，天然状态的蛋白质能量景观扩展的能量景观从基态过渡景观。
Phosphorylation is one of the most commonly used signaling mechanisms in biology. However, the molecular transition pathways between inactive and active states are poorly understood. Here we quantitatively characterize the free-energy landscape of activation of the signaling protein Nitrogen regulatory protein C (NtrC) by connecting functional protein dynamics of phosphorylation-dependent activation to protein folding. We show that only a rarely populated, pre-existing active conformation is capable of being phosphorylated. Atomistic details of a pathway for the complex conformational transition, inferred from molecular dynamics simulations is experimentally tested here by NMR dynamics experiments. We found that the loss of native stabilizing contacts during activation is compensated by non-native transient atomic interactions during the transition. The results demonstrate the power of combining computation with experimental corroboration to unravel atomistic details of native-state protein energy landscapes by expanding the energy landscape from the ground states to transition landscapes.
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DOI：
10.1098/rsta.2004.1496
发表时间：
2005-02-15
影响因子：
5
作者：
Karplus, M;Gao, YQ;Yang, W
通讯作者：
Yang, W
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
影响因子：
56.9
作者：
Boehr, David D.;McElheny, Dan;Wright, Peter E.
通讯作者：
Wright, Peter E.
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
2.9
作者：
FARROW, NA;MUHANDIRAM, R;KAY, LE
通讯作者：
KAY, LE