Gaieb Zied, Morikis Dimitrios
Department of Bioengineering, University of California, Riverside 92521, USA.
Department of Bioengineering, University of California, Riverside 92521, USA.
J Mol Graph Model. 2017 Jun;74:352-358. doi: 10.1016/j.jmgm.2017.04.012. Epub 2017 Apr 13.
Ligand-binding to G protein-coupled receptors (GPCRs) acts as the local driving force that initiates signal transduction through the receptor and mediates its conformational transitions and interactions with various intracellular effectors. In a recent study, We have shown that the binding of ligands CCL19 and CCL21 to CCR7 induces biased triggering of side chain-based molecular switches, which coordinate concerted transmembrane helical domain motions and transitioning of the receptor to distinct conformational states (Gaieb, Z., D.D. Lo, and D. Morikis. 2016. Molecular Mechanism of Biased Ligand Conformational Changes in CC Chemokine Receptor 7. Journal of Chemical Information and Modeling. 56: 1808-1822, DOI: 10.1021/acs.jcim.6b00367). To complement our previous study, we compare the results of the free (apo) CCR7 microsecond molecular dynamics simulations to those of the ligand-bound CCR7, and show that the apo receptor is found in conformational heterogeneity that only exhibits random fluctuations and lacks the coordinated helical motions seen in ligand-bound receptors. We conclude that ligand binding is responsible for coordinating the stochastic conformational nature of CCR7 into specific conformational states, initiated and propagated by specific physicochemical events.
配体与G蛋白偶联受体（GPCRs）的结合是启动通过该受体的信号转导并介导其构象转变以及与各种细胞内效应器相互作用的局部驱动力。在最近的一项研究中，我们已经表明配体CCL19和CCL21与CCR7的结合会诱导基于侧链的分子开关的偏向触发，这些开关协调跨膜螺旋结构域的协同运动以及受体向不同构象状态的转变（Gaieb，Z.，D.D. Lo和D. Morikis。2016年。CC趋化因子受体7中偏向配体构象变化的分子机制。《化学信息与建模杂志》。56：1808 - 1822，DOI：10.1021/acs.jcim.6b00367）。为补充我们之前的研究，我们将游离（无配体）CCR7的微秒级分子动力学模拟结果与配体结合的CCR7的结果进行比较，结果表明无配体受体存在构象异质性，仅表现出随机波动，缺乏配体结合受体中所见的协同螺旋运动。我们得出结论，配体结合负责将CCR7的随机构象性质协调为特定的构象状态，这些特定构象状态由特定的物理化学事件引发并传播。
