Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, 8093, Zürich, Switzerland.
Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 6, 14195, Berlin, Germany.
Angew Chem Int Ed Engl. 2020 Dec 1;59(49):22132-22139. doi: 10.1002/anie.202008734. Epub 2020 Sep 30.
Protein allostery is a phenomenon involving the long range coupling between two distal sites in a protein. In order to elucidate allostery at atomic resoluion on the ligand-binding WW domain of the enzyme Pin1, multistate structures were calculated from exact nuclear Overhauser effect (eNOE). In its free form, the protein undergoes a microsecond exchange between two states, one of which is predisposed to interact with its parent catalytic domain. In presence of the positive allosteric ligand, the equilibrium between the two states is shifted towards domain-domain interaction, suggesting a population shift model. In contrast, the allostery-suppressing ligand decouples the side-chain arrangement at the inter-domain interface 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 interplay between dynamics and function in the biological activity of proteins.
蛋白质变构是一种涉及蛋白质中两个远端部位之间长程偶联的现象。为了在原子分辨率上阐明酶 Pin1 的配体结合 WW 结构域的变构作用，从精确的核 Overhauser 效应（eNOE）计算了多态结构。在自由形式中，该蛋白质在两种状态之间进行微秒交换，其中一种状态倾向于与其亲本催化结构域相互作用。在正变构配体存在下，两种状态之间的平衡向结构域-结构域相互作用转移，提示存在群体转移模型。相比之下，变构抑制配体使结构域间界面处的侧链排列解耦，从而降低了结构域间相互作用。因此，这种机制是动态变构的一个例子。所呈现的不同作用模式突出了蛋白质动力学和功能之间相互作用在其生物学活性中的重要性。
