Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Chem Biol Drug Des. 2013 Nov;82(5):534-45. doi: 10.1111/cbdd.12179. Epub 2013 Aug 10.
Chemokine receptors belong to the membrane proteins that are included in many physiological phenomena. However, the mechanism of their action is unknown at the atomistic level in different aspects. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C-C chemokine receptor type 2, a prototypical chemokine receptor, is affected by lipid bilayer and an antagonist (INCB3344). This study includes homology modeling, molecular dynamics simulation in lipid bilayer, and docking. A detailed mechanism of INCB3344 has been described. Tyr 49, Trp 98, Tyr 120, His 121, and Glu 291 are proved to play important roles in binding. Integrating results obtained in this study and experimental data help us to suggest a two-step ligand-binding mechanism. The N-terminus of protein first sticks out from the extracellular domain suitable for the contact with the antagonist. Binding of ligand to this segment leads to the geometrical changes to facilitate the ligand interactions with extracellular loop 2 of C-C chemokine receptor type 2. Finally, the interactions occurring between extracellular loop 2 and ligand induce conformational changes in C-C chemokine receptor type 2 structure. These changes bring the ligand closer to the binding pocket, allowing the interaction between INCB3344 and the residues of active site.
趋化因子受体属于膜蛋白，包含在许多生理现象中。然而，它们在不同方面的作用机制在原子水平上尚不清楚。在这项研究中，我们利用计算流程来研究 C-C 趋化因子受体 2（一种典型的趋化因子受体）的结构如何受到脂质双层和拮抗剂（INCB3344）的影响的分子基础。本研究包括同源建模、在脂质双层中的分子动力学模拟和对接。详细描述了 INCB3344 的作用机制。证明 Tyr49、Trp98、Tyr120、His121 和 Glu291 在结合中起重要作用。整合本研究和实验数据的结果有助于我们提出两步配体结合机制。蛋白质的 N 端首先从细胞外结构域伸出，适合与拮抗剂接触。配体与该片段的结合导致构象变化，有利于配体与 C-C 趋化因子受体 2 的细胞外环 2 相互作用。最后，细胞外环 2 和配体之间发生的相互作用引起 C-C 趋化因子受体 2 结构的构象变化。这些变化使配体更接近结合口袋，允许 INCB3344 与活性位点的残基相互作用。
