Protein Allostery at Atomic Resolution.
Protein Allostery at Atomic Resolution.
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原子分辨率下的蛋白质变构。
DOI：
10.1002/anie.202008734
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发表时间：
2020-12-01
影响因子：
16.6
通讯作者：
Riek, Roland
中科院分区：
文献类型：
--
作者：
Strotz, Dean;Orts, Julien;Kadavath, Harindranath;Friedmann, Michael;Ghosh, Dhiman;Olsson, Simon;Chi, Celestine N.;Pokharna, Aditya;Guentert, Peter;Vogeli, Beat;Riek, Roland
受玻尔兹曼状态能量分布的限制，运动是生物分子固有的。为了详细了解蛋白质的功能，不仅需要 3D 结构，还需要对其动力学的描述。这对于阐明蛋白质变构的本质尤其重要。蛋白质变构是一种涉及蛋白质中两个远端位点之间的长程耦合的现象。在这里，我们研究了酶 Pin1，它具有两个灵活连接的结构域，即结合结构域 (WW) 和催化结构域 (PPI)，它们经历耦合结构重排。我们提出了自由形式和与两个拮抗配体复合的 WW 结构域的多态结构，这些结构是通过实验得出的精确核欧沃豪瑟效应 (eNOE) 速率确定的。我们发现这两个配体分别增强和抑制域间变构。在没有配体的情况下，蛋白质在两种状态之间经历微秒的交换，其中一种状态倾向于与催化结构域相互作用，而另一种状态则不然。在存在正变构配体的情况下，两种状态之间的平衡向配体作用模式移动，这表明莫诺提出的构象选择。相反，变构抑制配体将界面处的侧链排列解耦成反相关的方向和动力学，从而减少域间相互作用。因此，该机制是动态变构的一个例子。所提出的不同作用模式突出了蛋白质生物活性中动力学功能相互作用的力量。
Confined by the Boltzmann distribution of the energies of states, motion is inherent to biomolecules. For a detailed understanding of a protein’s function, not only the 3D structure but also the description of its dynamics is thus required. This is particularly important in the elucidation of the nature of protein allostery. Protein allostery is a phenomenon involving the long range coupling between two distal sites in a protein. Here we study the enzyme Pin1, which features two flexibly thethered domains, the binding domain (WW) and the catalytic domain (PPI), that undergo coupled structural rearrangements. We present multi-state structures of the WW domain of the free form and in complex with two antagonizing ligands determined by experimentally-derived exact nuclear Overhauser effect (eNOE) rates. We find that the two ligands respectively strengthen and suppress the inter-domain allostery. In the absence of ligands, the protein undergoes a micro-second exchange between two states, one of which is predisposed to interact with the catalytic domain, while the other one is not. In presence of the positive allosteric ligand, the equilibrium between the two states is shifted towards the mode of ligand action, suggesting conformational selection as proposed by Monod. In contrast, the allostery-suppressing ligand decouples the side-chain arrangement at the interface into anti-correlated orientation and dynamics, thereby reducing the inter-domain interaction. As such, this mechanism is an example of dynamic allostery. The presented distinct modes of action highlight the power of the dynamics-function interplay in the biological activity of proteins.
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影响因子：
4.8
作者：
Jacobs, DM;Saxena, K;Fiebig, KM
通讯作者：
Fiebig, KM
影响因子：
2.7
作者：
Chi, Celestine N.;Strotz, Dean;Voegeli, Beat
通讯作者：
Voegeli, Beat
影响因子：
64.8
作者：
Lindorff-Larsen, K;Best, RB;Vendruscolo, M
通讯作者：
Vendruscolo, M
DOI：
10.1073/pnas.0705097104
发表时间：
2007-10-02
影响因子：
11.1
作者：
Neudecker, Philipp;Zarrine-Afsar, Arash;Kay, Lewis E.
通讯作者：
Kay, Lewis E.
影响因子：
15
作者：
Olsson, Simon;Noe, Frank
通讯作者：
Noe, Frank